Anti-interleukin-23 receptor VHH antibodies and uses thereof

Abstract

Interleukin-23 receptor (IL23R) VHH antibodies are disclosed, as well as methods of making and using the same, e.g., for treatment of IL23-mediated diseases and disorders, including, e.g., gastrointestinal-related (Gl-related) diseases (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn's disease (CD)), a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection (e.g., a Salmonella infection or a Clostridium difficile infection), celiac disease, or pathogenic inflammation).

Description

PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1ANTI-INTERLEUKIN-23 RECEPTOR VHH ANTIBODIES AND USES THEREOFSEQUENCE LISTINGThe instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 6, 2025, is named 50474-371 WO2_Sequence_Listing_11_6_25 and is 54,380 bytes in size.FIELD OF THE INVENTIONThe invention relates to anti-interleukin-23 receptor (IL23R) VHH antibodies, and methods of making and using the same, including for treatment of an IL23-mediated disease or disorder (e.g., gastrointestinal-related (Gl-related) diseases (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn’s disease (CD)), a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection (e.g., a Salmonella infection or a Clostridium difficile infection), celiac disease, or pathogenic inflammation).BACKGROUND OF THE INVENTIONGastrointestinal-related (Gl-related) diseases (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn’s disease (CD)), colon cancer, small intestine cancer, gastric cancer, irritable bowel syndrome, gastrointestinal ulcer, gut-associated infections (e.g., Salmonella infection or Clostridium difficile infection), celiac disease, or pathogenic inflammation) accounted for over five million deaths in 2016 (World Health Organization). Virtually all Gl-related diseases are caused by, exacerbated by, or result in aberrant immune responses.Interleukin-23 receptor (IL23R) is a subunit of the receptor for the proinflammatory cytokine interleukin-23 (IL23). Signaling through IL23R is important for the expansion and maintenance of T helper 17 (Th17) cells and type 3 innate lymphoid cells (ILC3s) and IL23R has been implicated in various Gl- related diseases (e.g., IBD, e.g., UC or CD, and various Gl cancers). For example, IL23R has been implicated as a critical genetic factor in the inflammatory bowel disorders Crohn's disease and ulcerative colitis. See, Duerr et al. (2006) Science 314:1461 . Duerr and colleagues performed a genome-wide association study that found that the gene for IL23R was highly significantly associated with Crohn's disease, with an uncommon coding variant (Arg381 Gin) conferring strong protection against the disease. This genetic association confirmed prior findings (Yen el al. (2006) J. Clin. Investigation 116:1218), suggesting that IL23 and its receptor (including IL23R) are promising targets for new therapeutic approaches to treating IBD.Efforts have been made to identify therapeutic moieties that inhibit the IL23 pathway for use in treating IL23-related diseases and disorders. A number of antibodies that bind to IL23 or IL23R have been identified, including ustekinumab, a humanized antibody that binds IL23, which has been approved for the treatment of psoriasis (an autoimmune disease where the immune system attacks skin cells). More recently, polypeptide inhibitors that bind to IL23R and inhibit the binding of IL23 to IL23R have been identified (see, e.g., US Patent Application Publication No. US2013 / 0029907). Clinical trials in Crohn's Disease or psoriasis with ustekinumab and briakinumab (which target the common p40 subunit shared byPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1IL23 and interleukin-12) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL23) highlight the potential of IL23 signaling blockade to treat human inflammatory diseases. While these findings are promising, challenges remain with respect to identifying stable and selective agents that preferentially target the IL23 pathway in the intestine to treat IL23-mediated intestinal disorders, such as intestinal inflammation, e.g., intestinal bowel diseases and other Gl-related IL23-mediated disorders.SUMMARY OF THE INVENTIONDisclosed herein are novel polypeptide inhibitors that bind IL23R and inhibit IL23 binding and signaling and which are suitable for oral administration addressing the need for improved therapies that can ameliorate Gl-related disease through manipulation of immune responses.Disclosed herein are novel humanized camelid antibodies that were elicited to human IL23R protein in llamas. Not only do the novel antibodies have high affinity for the IL23R antigen, they block IL23 from binding to its receptor, IL23R, and are stable in the presence of pancreatin (a secretion of the pancreas rich in protein-degrading enzymes) : where native antibodies are digested like most other proteins within minutes, the disclosed antibodies can withstand pancreatin exposure for hours. This stability permits oral administration of the antibodies such that they reach their target tissues in the Gl tract intact. Surprisingly, these humanized camelid antibodies having such stability (specifically, resistance to Gl proteases, such as trypsin, chymotrypsin, and elastases) and enhanced affinity involved engineering residues of the antibodies that are not directly involved in binding to IL23R (e.g., framework mutations), but also those regions of the antibody which permit binding specificity (e.g., complementarity determining regions, CDRs). Also surprisingly, in at least one instance, an affinity-enhancing mutation also further enhances stability. Finally, the disclosed antibodies encompass further mutations that allow the antibodies to evade anti-VHH antibody antibodies (“anti-drug antibodies” (ADAs)) found in some subjects without decreasing the stability or affinity of the antibodies.In one aspect, the disclosure provides an isolated VHH antibody that specifically binds interleukin-23 receptor (IL23R), wherein the VHH antibody comprises a binding domain comprising the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1), wherein Xi is A or S; (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2is G or D; and (c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V.In some aspects, the binding domain comprises: (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1G (SEQ ID NO: 5), wherein Xi is V or T; and (c) a CDR-H3 comprising the amino acid sequence of KRPX1AGWX2TYDY (SEQ ID NO: 6), wherein Xi is D or G, and X2 is Q, S, or D.In some aspects, the binding domain comprises: (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8).PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1In some aspects, the binding domain comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMAWFRQAPGKEREFVAESWSSGTTYYGASVVGRFT MSRDDSKNTVYLQMNSLRAEDTAVYYCAAKRPDAGWQTYDYWGQGTLVQVQSA (SEQ ID NO: 9).In some aspects, the binding domain comprises an amino acid sequence having no more than six addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9.In some aspects, the binding domain comprises the following framework regions (FRs): (a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQX1GX2SLRLSCAASGX3TFS (SEQ ID NO: 10), wherein Xi is P or L, X2 is G or D, and X3 is F, G, Y, or R; (b) an FR-2 comprising the amino acid sequence of WFRQAPGKEREFVA (SEQ ID NO: 1 1 ); (c) an FR-3 comprising the amino acid sequence of RFTX1SRDDX2KNTVYLQMNSLX3X4EDTAVYYCAA (SEQ ID NO: 12), wherein Xi is M or I, X2is S or A, X3 is R or K, and X4 is A or P; and (d) an FR-4 comprising the amino acid sequence of WGQGTLVX1VX2S (SEQ ID NO: 13), wherein Xi is Q or T and X2 is Q or S.In some aspects, the binding domain comprises the following FRs: (a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 14); (b) an FR-2 comprising the amino acid sequence of WFRQAPGKEREFVA (SEQ ID NO: 1 1 ); (c) an FR-3 comprising the amino acid sequence of RFTMSRDDSKNTVYLQMNSLRAEDTAVYYCAA (SEQ ID NO: 15); and (d) an FR-4 comprising the amino acid sequence of WGQGTLVQVQS (SEQ ID NO: 16).In some aspects, the binding domain comprises a Q at position 1 10, a Q at position 1 12, and a C- terminal addition of an A at position 1 14 (Kabat numbering).In some aspects, the binding domain comprises the amino acid sequence of SEQ ID NO: 9.In some aspects, the binding domain consists of the amino acid sequence of SEQ ID NO: 9.In one aspect, the disclosure provides an isolated VHH antibody that specifically binds IL23R, wherein the VHH antibody comprises a binding domain comprising the amino acid sequence of SEQ ID NO: 9.In some aspects, the VHH antibody specifically binds human or cynomolgus (cyno) IL23R.In some aspects, the VHH antibody specifically binds both human and cyno IL23R.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD of about 1 nM or lower.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD between about 100 fM and about 1 nM.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD between about 750 fM and about 300 pM.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD between about 1 pM and about 200 pM.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD of about 60 pM.In some aspects, the KD is measured by a surface plasmon resonance assay at 37°C.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1In some aspects, the VHH antibody inhibits binding of IL23 to IL23R.In some aspects, the VHH antibody inhibits binding of IL23 to IL23R as determined by a cellbased functional assay.In some aspects, the VHH antibody is at least partially resistant to proteolysis by one or more proteases.In some aspects, the one or more proteases are elastase, trypsin, or chymotrypsin.In some aspects, the VHH antibody is at least partially resistant to proteolysis by elastase, trypsin, and chymotrypsin.In some aspects, at least about 5% of an initial amount of the VHH antibody is intact after at least one hour of exposure to elastase, trypsin, chymotrypsin, or pancreatin.In some aspects, at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to pancreatin.In some aspects, at least about 50% of an initial amount of the VHH antibody is intact after at least 20 hours of exposure to pancreatin.In some aspects, at least about 50% of an initial amount of the VHH antibody is intact after at least 3 hours of exposure to elastase.In some aspects, at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to trypsin.In some aspects, at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to chymotrypsin.In some aspects, resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.In some aspects, the in vitro protease stability assay uses pancreatin at a concentration of 10 mg / mL, elastase at a concentration of 1000 pg / mL, trypsin at a concentration of 500 pg / mL, and / or chymotrypsin at a concentration of 100 pg / mL.In one aspect, the disclosure provides an isolated VHH antibody that specifically binds to the same epitope on IL23R that is bound by a VHH antibody comprising a binding domain comprising the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1 ), wherein Xi is A or S; (b) a ODR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2is G or D; and (c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V.In one aspect, the disclosure provides an isolated VHH antibody that competes for binding with a VHH antibody comprising a binding domain comprising the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1 ), wherein Xi is A or S; (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2 is G or D; and (c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2is D or G, X3is Q, S, or D, and X4is T or V.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1In one aspect, the disclosure provides an immunoconjugate comprising the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R.In one aspect, the disclosure provides an isolated nucleic acid encoding the VHH antibody of an aspect described herein.In one aspect, the disclosure provides a vector comprising any of the isolated nucleic acids described herein.In one aspect, the disclosure provides a host cell comprising any of the vectors described herein. In some aspects, the host cell is a eukaryotic cell. In some aspects, the eukaryotic cell is a mammalian cell. In some aspects, the mammalian cell is a Chinese hamster ovary (CHO) cell. In some aspects, the host cell is a prokaryotic cell. In some aspects, the prokaryotic cell is Escherichia coli.In one aspect, the disclosure provides a method of producing a VHH antibody that specifically binds to IL23R, the method comprising culturing the host cell an aspect described herein in a culture medium under conditions that are suitable for producing the VHH antibody.In some aspects, the method further comprises recovering the VHH antibody from the host cell or the culture medium.In another aspect, the disclosure provides a composition comprising the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R.In some aspects, the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.In some aspects, the composition is a pharmaceutical composition.In some aspects, the composition is formulated for oral administration.In some aspects, the composition comprises one or more minitablets.In some aspects, the one or more minitablets each comprises the VHH antibody.In some aspects, the one or more minitablets are formulated to deliver a total dose of 150 mg of the VHH antibody.In some aspects, the one or more minitablets are formulated to deliver a total dose of 300 mg of the VHH antibody.In some aspects, the one or more minitablets comprise mannitol. In some aspects, the one or more minitablets comprise mannitol at a ratio of 5 mg of the VHH antibody to 1 mg of mannitol.In some aspects, the one or more minitablets comprise histidine.In some aspects, the one or more minitablets comprise histidine hydrochloride.In some aspects, the one or more minitablets are seal coated.In some aspects, the one or more minitablets are enteric coated.In some aspects, the one or more minitablets are formulated as a suspension in medium. In some aspects, the medium has a pH of about 3.5.In some aspects, the one or more minitablets are formulated in a capsule. In some aspects, the capsule is not coated.In some aspects, the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R, or the composition of an aspect described herein is for use as a medicament.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1In some aspects, the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R, or the composition an aspect described herein is for use in treating or delaying a gastrointestinal-related (Gl-related) disease.In some aspects, the Gl-related disease is an inflammatory bowel disease (IBD), a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut- associated infection, celiac disease, or pathogenic inflammation.In some aspects, any of the VHH antibodies or compositions described herein can be used in the manufacture of a medicament for treating a Gl-related disease.In some aspects, the disclosure provides a method for treating or delaying progression of a Gl- related disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the VHH antibodies or compositions described herein.In some aspects, the Gl-related disease is an IBD.In some aspects, the IBD is ulcerative colitis or Crohn’s disease.In some aspects, the IBD is ulcerative colitis.In some aspects, the ulcerative colitis is moderate to severe ulcerative colitis.In some aspects, the IBD is Crohn’s disease.In some aspects, the gut-associated infection is a Salmonella infection or Clostridium difficile infection.In some aspects, the VHH antibody or the composition is administered orally, intrarectally, mucosally, intravenously, intramuscularly, intradermally, transdermally, subcutaneously, percutaneously, intraarterially, intraperitoneally, intravitreally, topically, intralesionally, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intratumorally, intraperitoneally, peritoneally, intraventricularly, intracranially, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, intraorbitally, ocularly, intraocularly, juxtasclerally, subtenonly, superchoroidally, by inhalation, by injection, by eye drop, by implantation, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.In some aspects, the VHH antibody or the composition is administered orally.In one aspect, the disclosure provides a method of detecting human IL23R in a biological sample comprising contacting the biological sample with the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R, or the immunoconjugate of an aspect described herein under conditions permissive for binding of the VHH antibody or immunoconjugate to a naturally occurring human IL23R, and detecting whether a complex is formed between the VHH antibody or immunoconjugate and the naturally occurring human IL23R.In another aspect, the disclosure provides a kit comprising the VHH antibody of an aspect described herein, or a fragment thereof that specifically binds IL23R, the immunoconjugate of an aspect described herein, or the composition of an aspect described herein and a package insert comprising instructions for treating or delaying a Gl-related disease.In another aspect, the disclosure provides a VHH antibody or fragment thereof that specifically binds IL23R, wherein the antibody has at least one of the following characteristics: (a) specifically binds human IL23R and cynomolgus (cyno) IL23R; (b) specifically binds both human and cyno IL23R with a KDPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 of about 1 nM or lower, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (c) specifically binds both human and cyno IL23R with a KD between about 100 fM and about 1 nM, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (d) specifically binds both human and cyno IL23R with a KD between about 750 fM and about 300 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (e) specifically binds both human and cyno IL23R with a KD between about 1 pM and about 200 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (f) specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (g) inhibits binding of IL23 to IL23R as determined by a cell-based functional assay; (h) is at least partially resistant to proteolysis by pancreatin or one or more of elastase, trypsin, or chymotrypsin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; (i) at least about 5% of about 10- 15 pg of the VHH antibody is intact after at least one hour of exposure to elastase, trypsin, chymotrypsin, or pancreatin, wherein the pancreatin is at a concentration of about 10 mg / mL, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; (j) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 4 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; (k) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; or (I) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.In some aspects, the VHH antibody specifically binds both human and cyno IL23R with a KD of about 60 pM, and the KD is measured by a surface plasmon resonance assay at 37°C.In some aspects, the VHH antibody specifically binds both human and cyno IL23R, wherein at least about 50% of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.In some aspects, at least about 50% of 10-15 pg of the antibody is intact.In some aspects, the pancreatin is at a concentration of about 10 mg / mL.In some aspects, the VHH antibody specifically binds both human and cyno IL23R, wherein at least about 50% of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.In some aspects, at least about 50% of 10-15 pg of the VHH antibody is intact.In some aspects, the VHH antibody has the following characteristics: (a) specifically binds human IL23R and cynomolgus (cyno) IL23R; (b) specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C; (c) inhibits binding of IL23 to IL23R as determined by a cell-based functional assay; (d) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C;PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 and (e) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.In some aspects, the VHH antibody is a humanized or chimeric antibody. In some aspects, the VHH antibody is a full-length antibody. In some aspects, the VHH antibody is a VHH antibody fragment that specifically binds IL23R. In some aspects, the VHH antibody is a VHH single-domain antibody.In some aspects, the VHH antibody is not significantly bound by pre-existing anti-VHH antibodies in a subject.In some aspects, the subject is a human.In some aspects, the VHH antibody specifically binds to an epitope in the D1 domain of human IL23R.In some aspects, the VHH antibody comprises an Fc region. In some aspects, the Fc region is an IgG Fc region. In some aspects, the Fc region or IgG Fc region is human. In some aspects, the amino terminus of the Fc region is fused to the carboxy terminus of the binding domain of the VHH antibody.In some aspects, the binding domain of the VHH antibody is fused to an anti-serum albumin antibody. In some aspects, the anti-serum albumin antibody is human.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1A is a graph showing a human peripheral blood mononuclear cell (hPBMC) cell-based assay measuring human IL17F production in the presence of IL23 and anti-IL23R VHH antibodies. Gray bars indicate anti-IL23R VHH antibodies that were able to inhibit IL23 signaling.FIG. 1 B is a graph showing the inhibitory activity of the anti-IL23R VHHs in the IL23-IL23R blocking ELISA assay.FIG. 2 is a collection of images showing a gel-based assay measuring cleavage of anti-IL23R VHH antibodies by pancreatin. Seven purified VHHs (containing His tags) were incubated with (+) or without (-) pancreatin for 0, 1 , and 4 hours (hrs) and analyzed by SDS-PAGE. Only 2A8 and 2F1 show intact VHH at 1 hour, whereas all other VHHs are fully degraded.FIG. 3 is a heatmap showing mutational tolerance of full-length 2A8 VHH at every position. NGS analysis was performed on a saturation mutagenesis library of 2A8 before and after selections against IL23R. Mutations are colored as follows: enriched (pink / red), neutral (white), de-enriched (blue).FIG. 4 is an image showing a gel-based assay measuring cleavage of humanized 2A8 (h2A8) antibody variants by trypsin. Humanized 2A8 and two single amino acid variants (R27F and V97P) were incubated with trypsin for 0, 1 , and 2 hours and analyzed by SDS-PAGE. Both mutations, R27F and V97P, increase trypsin stability as shown by less pronounced VHH fragments.FIGS. 5A and 5B are a series of images showing a gel-based assay measuring cleavage of h2A8, h2A8-R27F+V97P, or h2A8-S100bQ antibodies by trypsin or chymotrypsin. Humanized 2A8 and the dual R27F+V97P variant were incubated with trypsin (FIG. 5A) for 0, 1 , and 2 hours and analyzed by SDS-PAGE. The dual R27F+V97P variant exhibited increased trypsin stability as shown by less pronounced VHH fragments. Humanized 2A8 and the S100bQ variant were incubated with chymotrypsinPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1(FIG. 5B) for 0, 1 , and 2 hours and analyzed by SDS-PAGE. The S1 OObQ variant exhibited increased chymotrypsin stability as shown by less pronounced VHH fragments.FIG. 6 is an image showing a gel-based assay measuring cleavage of h2A8 and h2A8- R27F+V97P (v23) antibodies by pancreatin. Humanized 2A8 and the dual R27F+V97P variant were incubated with pancreatin for 0, 1 , and 6 hours and analyzed by SDS-PAGE. The dual R27F+V97P variant exhibited increased pancreatin stability as shown by less VHH fragments.FIG. 7 is an image showing a gel-based assay measuring cleavage of 2A8v23 (R27F+V97P) antibody by elastase. The His-tagged dual R27F+V97P variant was incubated with elastase for 0, 1 , and 3 hours and analyzed by SDS-PAGE. The lower shift in MW observed at 1 and 3 hrs compared to 0 hrs was due to removal of the His-tag. However, the VHH domain remained intact.FIG. 8 is an image showing a gel-based assay measuring cleavage of His-tagged 2A8 antibody variants by chymotrypsin. Several mutations (S53E, S100bD, and S100bQ) were introduced into 2A8v23 (R27F+V97P). Each VHH was incubated with chymotrypsin for 0, 15, or 60 minutes and analyzed by SDS-PAGE. Both S100bD and S100bQ increase the stability of v23 in chymotrypsin.FIG. 9 is an image showing a gel-based assay measuring cleavage of His-tagged 2A8 antibody variants by pancreatin. Several mutations (S53E, S100bD, and S100bQ) were introduced into 2A8v23. Each VHH was incubated with pancreatin for 2, 4, or 6 hours and analyzed by SDS-PAGE. The addition of S1 OObQ leads to the best stability of v23 in pancreatin.FIG. 10 is an image showing a gel-based assay measuring cleavage of the h2A8v82 antibody with and without a His-tag by pancreatin. 2A8v82 (R27F+V97P+S1 OObQ) with and without a C-terminal His tag were incubated with pancreatin for 0, 4, 9, or 20 hours and analyzed by SDS-PAGE. Removal of the His tag significantly improves the pancreatin stability of the VHH.FIG. 11 is an image showing a gel-based assay measuring cleavage of His-tagged 2A8 antibody single-substitution variants by pancreatin. The parental 2A8 and twelve variants were incubated with pancreatin for 25 minutes and analyzed by SDS-PAGE. A majority of the variants exhibited slightly improved stability. Several mutations (V48M, V78F, and V63Y) either decrease or have no effect on VHH stability.FIG. 12 is a set of images showing a gel-based assay measuring cleavage of His-tagged 2A8 antibody combination-substitution variants by pancreatin. Fourteen variants of 2A8v82 were incubated with pancreatin for 8 (top) or 17 (bottom) hrs and analyzed by SDS-PAGE. Several variants (v122, 123, 128, and 129) exhibit improved stability. Lower band slightly below 14 kDa is due to removal of His-tag.FIG. 13 is an image showing a gel-based assay measuring cleavage of 2A8v82 and 2A8v129 antibodies by pancreatin. Untagged humanized 2A8 and variants v82 and v129 were incubated with pancreatin for 0, 1 , and 18 hours and analyzed by SDS-PAGE. Both variants exhibit improved stability compared to WT h2A8.FIG. 14 is a graph showing binding of pre-existing anti-VHH antibodies to 2A8v129 and 2A8v134. Binding to pre-existing anti-VHH antibodies in human sera from 96 individual healthy donors was analyzed by ELISA. 2A8v134 exhibits significantly reduced binding.FIG. 15 is a sequence alignment of 2A8v134 with parental 2A8WT, 2A8v23, 2A8v82, and 2A8v129.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1FIG. 16 is an image showing a gel-based assay measuring cleavage of 2A8v129 and 2A8v134 antibodies by trypsin. Humanized 2A8 and two variants (v129 and v134) were incubated with trypsin for 0, 1 , and 4 hours and analyzed by SDS-PAGE. Both variants exhibit improved stability.FIG. 17 is an image showing a gel-based assay measuring cleavage of 2A8v129 and 2A8v134 antibodies by chymotrypsin. Humanized 2A8 and two variants (v129 and v134) were incubated with chymotrypsin for 0, 1 , and 4 hours and analyzed by SDS-PAGE. Both variants exhibit improved stability.FIG. 18 is an image showing a gel-based assay measuring cleavage of 2A8v129 and 2A8v134 antibodies by pancreatin. Humanized 2A8 and two variants (v129 and v134) were incubated with pancreatin for 0, 1 , and 24 hours and analyzed by SDS-PAGE. Both variants exhibit improved stability.FIGS. 19A-19C show graphs showing percent inhibition of the IL23-IL23R interaction. The IL23:IL23R blocking assay was used to measure percent inhibition of the antibodies (2A8v129 or m20D7) or protease-stable cyclic peptides (26145 and 26149) without the washing step (FIG. 19A) and with the washing step (FIG. 19B). A comparison of 2A8v134 and m20D7 blocking assay with the washing step is shown in FIG. 19C.FIGS. 20A and 20B show graphs showing percent inhibition of IL17F secretion from the human primary T cell-based IL23R blockade assay using the m20D7 (FIG. 20A) and the VHH (2A8v134) (FIG. 20B) antibodies at varying concentrations.FIGS. 20C-20F show graphs showing percent recovery of WT 2A8 and 2A8v134 in the presence of biological matrices. Percent recoveries of WT 2A8 (black) and 2A8v134 (gray) over time in pancreatin (FIG. 20C), mouse intestinal fluid (FIG. 20D), mouse feces (FIG. 20E), and human feces (FIG. 20F) are shown.FIG. 21 A is a collection of immunohistochemistry images showing VHH 2A8v134 penetration into small intestine and colon of hlL23R ex3 knock-in mice treated with DSS for 7 days. Gl tract were fixed in neutral buffered formalin, sectioned, and stained for VHH with anti-VHH framework antibody.FIGS. 21 B-21G show graphs showing VHH 2A8v134 in serum (FIG. 21 B), urine (FIG. 21 C), and enhanced penentration across the damaged epithelial barrier of gut tissue. hlL23R ex3 knock-in mice were untreated or treated with DSS for 7 days, and received VHH 2A8v134 orally. At the indicated times, serum and tissue from ileum and colon were harvested. The tissue was homogenized, and the VHH in serum and tissue homogenate was measured by ELISA. The VHH in mesenteric lymph nodes (FIG. 21 D) and Peyer’s patches (FIG. 21 E) are shown, as well as the VHH in ileum (FIG. 21 F) and colon (FIG. 21 G). LN = lymph nodes.FIG. 21 H is a heat map showing VHH 2A8v134 abundance in the small intestine and colon after oral administration to mice pre-treated with or without DSS. The presence of the VHH in mucus (MUCUS), mucus only, in focal areas of epithelium (Focal EP), or in focal areas of the mucus (FOCAL MUCUS) are indicated. The absence of the VHH is also indicated (NONE). “ID” represents individual mice. “No tissue” represents missing tissue. Scale from highest to lowest abundance of the VHH: +++, ++, +, + / -, NONE.FIGS. 211 and 21 J are a series of graphs showing transepithelial electrical resistance (Teer) (FIG. 211) and VHH permeability (FIG. 21 J) of monolayers of colonic epithelial cells. Human colonic epithelial cells were established in monolayers, differentiated in a trans-well assay, and treated with thePATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 indicated cytokines for 24 h. Asterisks indicate statistical significance as determined using student t-tests. DSS = dextran sodium sulfate.FIG. 22A is a graph showing / / 22 mRNA levels induced by exogenous hlL23 in the colon of hlL23R ex3 knock-in mice with intact gut epithelia. hlL23R ex3 knock-in mice received VHH 2A8v134 orally at -18, -3, and 0 h, then intravenously injected with hlL23. Colon was harvested and analyzed for 1122 gene expression. Asterisks indicate statistical significance as determined using student t-tests. m20D7 = anti-hlL23R IgG.FIGS. 22B-22F show graphs showing that VHH inhibited signaling induced by exogenous hlL23. VHH showed inhibition at various Gl segments. hlL23R ex3 knock-in mice were treated with DSS for 7 days, and received 500 pg of VHH 2A8v134 orally at -18, -3, and 0 h. Mice were intravenously injected with hlL23, and proximal colon (FIG. 22B), middle colon (FIG. 22C), distal colon / rectum (FIG. 22D), mesenteric lymph nodes (FIG. 22E), and Peyer’s patches (FIG. 22F) were harvested 3 h later, and analyzed for gene expression of IL23-downstream factors ( / / 2 and / / / Zf mRNA). Asterisks indicate statistical significance as determined using student t-tests.FIGS. 22G-22K show graphs showing that VHH inhibited signaling induced by exogenous hl L23 in a dose-dependent manner. hlL23R ex3 knock-in mice were treated with DSS for 7 days, and received the indicated amounts of VHH 2A8v134 orally at -18, -3, and 0 h. Mice were intravenously injected with hlL23, and serum (FIG. 22G), colon (FIG. 22H), ileum (FIG. 22I), mesenteric lymph nodes (FIG. 22J), and spleen (FIG. 22K) were harvested 3 h later, and analyzed for gene expression of IL23-downstream factors (1122 and / / / Zf mRNA). Asterisks indicate statistical significance as determined using student t- tests.FIGS. 23A-23H show graphs showing that VHH-inhibited signaling that was induced by endogenous mouse IL23 in an anti-CD40-induced colitis model. hlL23R ex3 knock-in Rag2 knock-out mice were pre-treated with low-dose DSS for 4 days, and received anti-CD40 agonistic antibody on Day 0. The mice were treated with VHH 2A8v134 3 times per day from Day 2 or with anti-hlL23R IgG (m20D7) on Day 3 and 5. Percent body weight change in the mice on days after anti-CD40 treatment is shown (FIG. 23A). On Day 6, gene expression analysis of IL23-downstream factors on harvested tissue from colon (FIGS. 23B-23F) and ileum (FIGS. 23G and 23H). Asterisks indicate statistical significance as determined using student t-tests.FIG. 24 is a collection of flow cytometry graphs showing that VHH 2A8v134 can inhibit IL23- induced phosphorylation of STAT3 in human blood. Donor healthy human whole blood was incubated with either control antibody or VHH 2A8v134, and stimulated with human IL23. As a positive control for STAT3 phosphorylation, human whole blood was treated with hlL6 and soluble hlL6Ra. Phosphorylation of STAT3 in CD45RO+population was analyzed by FACS. CD45RO+gated cells were labeled with anti- 004 (FITC) and anti-phospho-Y705-STAT3 (Alexa Fluor® 647).FIGS. 25A and 25B demonstrate that orally administered VHH 2A8v134 can inhibit IL23-induced phosphorylation of STAT3 in cynomolgus monkey. Cynomolgus monkeys orally received enteric-coated pills containing VHH 2A8v134 on Day 0, and daily from Day 4 to Day 7, or control pills. Representative flow cytometry plots for phosphorylated STAT3 (pSTAT3 Y705) induced by ex vivo stimulation with hlL23 in whole blood harvested at pre-dose or 8 h after inoculation. A representative plot of the CD3+ / pSTAT3+PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1T cell population is shown (FIG. 25A). Time course of pSTAT3 induction compared to pre-dose (FIG. 25B).FIG. 25C is a graph showing that VHH concentration in serum of cynomolgus monkey after oral administration fit to the estimated concentration by a physiological-based pharmacokinetic modeling and simulation approach. Cynomolgus monkey received enteric-coated pill containing VHH 2A8v134 on Day 0, and daily from Day 4 to Day 7. VHH concentrations in serum were analyzed by ELISA (VHH 2A8v134 detected in serum) and compared to the serum PK modeling prediction (Serum PK prediction).FIGS. 25D and 25E shows that VHH recovery from rectum / distal colon contents of cynomolgus monkeys was much greater than from stool samples. VHH content in the stool and rectum / distal colon are shown (FIG. 25D). VHH content in the rectum from PBPK simulation is shown, indicating VHH content over time for the estimated half-lives (t1 / 2). The observed VHH content (rectum observation) is also shown (FIG. 25E).FIG. 26 is a schematic of a pharmacokinetic (PK) model that outlines the process following intravenous (IV) or oral administration of a VHH. Drug dissolution in the formulation compartment is described by the Weibull dissolution model, with only the dissolved drug being absorbable. The absorption fraction varies over time, reflecting a higher fraction in the small intestine and a lower fraction in the colon. Once absorbed, the drug distributes from the central compartment into two peripheral compartments and undergoes systematic clearance. Ka = absorption rate constant; CLD1 = distribution clearance 1 ; CLD2 = distribution clearance 2 ; CL = systemic clearance; Abs Frac = time dependent absorption fraction; IV - intravenous.FIG. 27 is a schematic showing isolation of poopernatant from a stool slurry.FIGS. 28A-28D are a set of graphs showing a pharmacokinetic model, which incorporates the Weibull dissolution and a time-dependent absorption fraction, that effectively characterizes the pharmacokinetic observations for both IV and two oral (PO) arms with single and double coat formulations. FIG. 28A shows the single coat formulation facilitates rapid dissolution, optimizing absorption in the small intestine. In contrast, the double coat formulation delays absorption, allowing it to bypass the small intestine, with primary absorption occurring in the colon. FIG. 28B shows IV PK data are well-characterized by a three-compartment model, providing estimates of systematic PK parameters such as clearance and volume distribution. FIG. 28C shows the single coat formulation leads to rapid absorption, an early Cmax, and higher systemic exposure of VHH. FIG. 28D shows the double coat formulation significantly delays absorption, resulting in lower systemic exposure of VHH. h = hour.FIG. 29 is a set of graphs showing individual cumulative fecal recovery following a single PG-150 mg of VHH 2A8v134 (immediate release (IR) capsule), in cynomolgus monkeys. Dashed lines represent 0.1%, 1%, 10%, and 100% of dose recovery, respectively, from bottom to top. PO = oral; h = hours.FIG. 30 is a set of graphs showing individual cumulative fecal recovery following a single PG-150 mg of VHH 2A8v134 (enteric capsule), in cynomolgus monkeys. Dashed lines represent 0.1%, 1%, 10%, and 100% of dose recovery, respectively, from bottom to top. PO = oral; IR = immediate release; h = hours.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1FIG. 31 is a set of graphs showing individual mass balance of VHH 2A8v134 in Gl lumen contents following two doses of PG-150 mg doses in cynomolgus monkeys. Dashed lines representO.1%, 1%, 10%, and 100% of dose recovery, respectively, from bottom to top. PO = oral.FIG. 32 is a graph showing percent gated pSTAT3+ T-cells following (CD3+ / pSTAT3+) in vitro recombinant human IL-23 (rhulL-23) stimulation. CD3 = cluster of differentiation 3; pSTAT = phosphorylated signal transducer and activator of transcription 3.FIGS. 33A and 33B are sets of Anti-VHH Western blots of IL23RVHHv134 showing stability of the V134 (VHH 2A8v134) and the initial version (V1) in vitro from animal Nos. 1501 and 2001 at 0, 1 , 4, 8, and 24 hours after anaerobic incubation in cynomolgus monkey poopernatant (FIG. 33A) or of V134 from animal Nos. 1501 and 2001 at 0, 6, 24, and 48 hours after anaerobic incubation in cynomolgus monkey stool slurry (FIG. 33B). Molecular weights of 8 and 15 kilodaltons are shown to the left of the gels.DETAILED DESCRIPTION OF THE INVENTIONDisclosed herein are improved antibodies that bind to IL23R. The VHH antibodies provided herein have unexpectedly advantageous properties, including high affinity for both human and cynomolgus monkey (cyno) IL23R, the ability to inhibit binding of IL-23 to IL23R, stability at low pH, resistance to proteolysis (e.g., resistance to proteolysis by elastase, trypsin, chymotrypsin, or pancreatin), the ability to evade binding by pre-existing anti-VHH antibodies, and the ability to treat IL23-mediated diseases and disorders, such as, e.g., Gl-related IL23-mediated diseases and disorders (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn’s disease (CD)), colon cancer, small intestine cancer, gastric cancer, irritable bowel syndrome, gastrointestinal ulcer, gut-associated infections (e.g., a Salmonella infection or a Clostridium difficile infection), celiac disease, or pathogenic inflammation).I. GENERAL TECHNIQUESThe techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual3b edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.l. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather andP.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C .A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: APATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).II. DEFINITIONSUnless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention 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.As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and / or parameters unless otherwise noted. Before the present methods and uses therefore are described, it is to be understood that disclosed subject matter is not limited to the particular methodology, protocols, cell lines, animal species or genera, constructs, and reagents described as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosed subject matter.Aspects and embodiments described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments.The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. For example, reference to “an isolated peptide” means one or more isolated peptides."Comprise," or variations such as "comprises" or "comprising," implies the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.The term “IL23R” or “interleukin-23 receptor” refers herein to any native IL23R from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term also encompasses naturally occurring variants of IL23R, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human IL23R is be found under UniProt Accession Number Q5VWK5 (SEQ ID NO: 17).The term “Fc region,” “Fc domain” or “Fc” refers to a C-terminal non-antigen binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native Fc regions and variant Fc regions. In certain embodiments, a human IgG heavy chain Fc region extends from Cys226 to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present, without affecting the structure or stability of the FcPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 region. Unless otherwise specified herein, numbering of amino acid residues in the IgG or Fc region is according to the EU numbering system for antibodies, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.The term "IL23-mediated disease or disorder," used interchangeably with "IL23-mediated disease" herein, as well as grammatical variants thereof, refers to any pathology known in the art to be caused by (alone or in association with other mediators), exacerbated by, associated with, or prolonged by abnormal levels of IL23 or abnormal activation of the IL23 pathway in the subject having the disorder. Non-limiting examples include IL23-mediated inflammatory bowel diseases (e.g., ulcerative colitis (UC) and Crohn' s disease (CD)), as well as pulmonary diseases, chronic inflammatory skin diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, or cancer. In some aspects, the IL23-mediated inflammatory bowel disease is CD or UC. In some aspects, the IL23-mediated pulmonary disease is asthma (e.g., allergic asthma, atopic asthma, corticosteroid naive asthma, chronic asthma, corticosteroid resistant asthma, corticosteroid refractory asthma, asthma due to smoking, or asthma uncontrolled on corticosteroids), idiopathic pulmonary fibrosis (I PF) , or chronic obstructive pulmonary disease (COPD). In some aspects, the IL23-mediated chronic inflammatory skin disease is atopic dermatitis, allergic contact dermatitis, eczema, psoriasis, alopecia areata, or palmoplantar pustulosis. In some aspects, the IL23-mediated inflammatory disease is psoriatic arthritis, anklyosing spondylitis, arthritis, rheumatoid arthritis (RA), a rheumatic disorder, ANCA vasculitis, Bechet' s disease, or autoimmune thyroiditis. In some aspects, the IL23-mediated autoimmune disease is multiple sclerosis (MS), Sjogren' s syndrome (SS), systemic lupus erythematosus (SLE), autoimmune encephalomyelitis, collagen-induced arthritis, or type 1 diabetes mellitus. In some aspects, the IL23-mediated neurodegenerative disease is Alzheimer's disease. In some aspects, the IL23 -mediated cancer is melanoma, colorectal cancer, stomach cancer, myeloma, prostate cancer, colitis-associated cancer, ovarian cancer, oral cancer, esophageal cancer, leukemia hepatitis B virus (HBV)-related hepatocellular carcinoma, breast cancer, lung cancer, and nasopharyngeal cancer. In some aspects, the IL23 -mediated disease or disorder is a microbial infection, including, e.g., mycobacterial disease, or leishmaniasis. In some aspects, the IL23 -mediated disease or disorder is a fungal or a viral infection, e.g., a coronavirus infection (see, e.g., Khader et al., Mucosal Immunol 2(5): 403-41 1 (2009)).As used herein, the term "Gl-related disease" refers to an IL23-mediated disease or disorder involving the gastrointestinal (Gl) tract or accessory organs of digestion, including the mouth, esophagus, stomach, small intestine, gallbladder, pancreas, appendix, large intestine, rectum, anus, or liver. In some embodiments, the Gl-related disease is inflammatory bowel disease (IBD) , cancer of the Gl tract, such as colon cancer, small intestine cancer, and gastric cancer, including, e.g., papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma and other poorly cohesive carcinomas; mixed carcinoma, adenosquamous carcinoma, squamous cell carcinoma, hepatoid adenocarcinoma, carcinoma with lymphoid stroma, choriocarcinoma, carcinosarcoma, parietal cell carcinoma, malignant rhabdoid tumor, mucoepidermoid carcinoma, paneth cell carcinoma, undifferentiated carcinoma, mixed adeno-neuroendocrine carcinoma, endodermal sinus tumor, embryonal carcinoma, pure gastric yolk sac tumor, oncocytic adenocarcinoma, gastrointestinal stromal tumor,PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 leiomyosarcoma, carcinoid tumor, and gastric lymphoma; irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation. In some embodiments, the IBD is ulcerative colitis (UC) or Crohn’s disease (CD). In some embodiments, the gut-associated infection is a Salmonella infection or Clostridium difficile infection. In other cases, a Gl-related disease pertains to epithelial integrity, epithelial proliferation, differentiation and / or migration in the intestine, graft versus host disease (GVHD), e.g., acute or chronic GVHD such as Gl GVHD.The term “ulcer” is a site of damage to the skin or mucous membrane that is often characterized by the formation of pus, death of tissue, and is frequently accompanied by an inflammatory reaction.The term “gastrointestinal tract,” “Gl tract,” “gut,” “alimentary canal,” or “digestive tract, ’’used herein broadly encompasses all organs involved in digestion. The Gl tract includes the mouth, esophagus, stomach, small intestine, gallbladder, pancreas, appendix, large intestine, rectum, anus, and liver.The term “intestine” as used herein broadly encompasses the small intestine and large intestine.An “acceptor human framework” for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.“Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., a ligand or an antibody) and its binding partner (e.g., a receptor or an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., IL23 and IL23R). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described herein.The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.“Antibody fragments” comprise a portion of an antibody, preferably the antigen binding or variable region of the antibody. Examples of antibody fragments include VHHs, single-domain antibodies, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see U.S. Patent No. 5,641 ,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062

[1995] ); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.The term “single-domain antibody” or “sdAb” refers to a single antigen-binding domain having three complementarity determining regions (CDRs). The sdAb alone is capable of binding to the antigenPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 without pairing with a corresponding CDR-containing polypeptide. In some cases, single-domain antibodies are engineered from camelid HCAbs and are referred to as “VHHs” (defined below). Camelid sdAb is one of the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993); Greenberg et al., Nature 374:168-73 (1995); Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). The term “VHH” or “variable domain of the heavy chain of a heavy chain antibody” refers to a single, heavy chain variable domain of a heavy chain antibody. VHH molecules can be derived from antibodies raised in Camelidae species, for example, camel, llama, vicuna, dromedary, alpaca and guanaco. A basic VHH has the following structure from the N-terminus to the C-terminus: FR1 -CDR1 -FR2-CDR2-FR3-CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3.An “antibody that binds to the same epitope” as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein.The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgGz, IgGs, lgG4, IgAi , and IgAz. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, e, y, and p, respectively.The term “constant domain” refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. For example, a camelid heavy chain antibody contains a CH2 and a CH3. For example, an IgG constant domain contains the CH1 , CH2 and CH3 domains (collectively, CH) of the heavy chain and the CHL (or CL) domain of the light chain.The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and the various antitumor or anticancer agents disclosed below.The term “anti-cancer therapy” refers to a therapy useful in treating cancer (e.g., cervical cancer). Examples of anti-cancer therapeutic agents include, but are limited to, e.g., immunomodulatory agents (e.g., an immunomodulatory agent (e.g., an agent that decreases or inhibits one or more immune co- inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1 , PD-1 ,PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®)), an anti-TIGIT antagonist antibody, or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1 106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR), such as an OX-40 agonist, e.g., an OX-40 agonist antibody), chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenesis agents, apoptotic agents, anti-tubulin agents, and other agents to treat cancer.“Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 1 and calicheamicin w1 1 (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, III.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors (e.g., an anaplastic lymphoma kinase (Aik) inhibitor, such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, andPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1VAXID®; PROLEUKIN®, rlL2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds described include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, peefusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT- 874 / J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively humansequence, full-length lgG1 A antibody genetically modified to recognize interleukin-12 p40 protein.Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO 96 / 40210, Imclone Systems Inc.); IMC-1 1 F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891 ,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1 .1 , E2.4, E2.5, E6.2, E6.4, E2.1 1 , E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29) :30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521 ,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041 , 6,002,008, and 5,747,498, as well as the following PCT publications: WO98 / 14451 , WG98 / 50038,PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1W099 / 09016, and WO99 / 24037. Particular small molecule EGFR antagonists include OSI-774 (CP- 358774, erlotinib, TARCEVA® Genentech / OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 -methyl-piperidin-4-yl)-pyrimido[5,4- d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1 -phenylethyl)amino]-1 H-pyrrolo[2,3- d]pyrimidin-6-yl]-phenol) ; (R)-6-(4-hydroxyphenyl)-4-[(1 -phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4- fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]- 6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Aik) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP261 13, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR- overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI- 1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide) ; tyrphostines containing nitrothiophene moieties; PD- 0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521 ; Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1 C1 1 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999 / 09016 (American Cyanamid); WO 1998 / 43960 (American Cyanamid); WO 1997 / 38983 (Warner Lambert); WO 1999 / 06378 (Warner Lambert); WOPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-11999 / 06396 (Warner Lambert); WO 1996 / 30347 (Pfizer, Inc); WO 1996 / 33978 (Zeneca); WO 1996 / 3397 (Zeneca) and WO 1996 / 33980 (Zeneca).Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective antiinflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL1 ) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL6) blockers such as tocilizumab; Interleukin 13 (IL13) blockers; Interferon alpha (IFN) blockers such as rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1 / p2 blockers such as anti- lymphotoxin alpha (LTa); radioactive isotopes (e.g., At21 1 , 1131 , 1125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9- tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g., celecoxib or etoricoxib), proteosome inhibitor (e.g., PS341 ); CCI-779; tipifarnib (R1 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone;PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.“Effector functions” or “effector activities” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibodydependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.An “effective amount” or “therapeutically effective amount” of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.By "reduce or inhibit," e.g., with respect to inhibiting IL23R, is meant the ability to cause an overall decrease, preferably of 20% or greater, more preferably of 50% or greater, and most preferably of 75%, 85%, 90%, 95%, or greater.A “suboptimal amount” refers to the amount less than the optimal amount of a therapeutic agent typically used for a certain treatment. When two therapeutic agents are given to a subject, either concurrently or sequentially, each therapeutic agent can be given at a suboptimal amount as compared to the treatment when each therapeutic agent is given alone."Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1 - H1 (L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein, which may include, for example, a VHH antibody fused to an Fc region, such as a VHH-Fc antibody fusion, as described herein.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. The transformed cell includes transiently or stably transformed cell. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein. In certain embodiments, the host cell is transiently transfected with the exogenous nucleic acid. In certain other embodiments, the host cell is stably transfected with the exogenous nucleic acid.A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991), vols. 1 -3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non- human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”) and / or form structurally defined loops (“hypervariable loops”) and / or contain the antigencontacting residues (“antigen contacts”). Generally, antibodies comprise six HVRs: three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3). Exemplary HVRs herein include:(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91 -96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987));(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31 -35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); andPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1(d) combinations of (a), (b), and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra. In certain embodiments, an antibody (e.g., a VHH antibody) can contain three HVRs.An “immunoconjugate” is an antibody or a fragment of an antibody (e.g., VHH antibody, or antibody fragment thereof) conjugated to one or more heterologous molecule(s) (e.g., a therapeutic molecule (e.g., chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof)) or a molecule used for detection (e.g., radioactive isotopes (e.g., zirconium 89), fluorophores, enzymes (e.g., horseradish peroxidase or luciferase))), including but not limited to a cytotoxic agent or a molecule used for detection.An “individual,” “subject” or “patient” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual, subject or patient is a human.An “isolated” protein (e.g., VHH antibody) is one which has been separated from the environment of a host cell that recombinantly produces the fusion protein. In some embodiments, a protein is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. The naked antibody may be present in a pharmaceutical formulation.“Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native camelid heavy chain antibodies are homodimeric proteins of about 80,000 Daltons, composed of two identical heavy chains composed of a VHH and two constant domains (CH2 and CH3). For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each IgG heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each IgG light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include, without limitation, a native sequence human IgG 1 Fc region (non-A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region, as well as naturally occurring variants thereof.A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, morePATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 preferably at least about 95% homology therewith. In certain embodiments, the variant Fc region is not glycosylated.With regard to the binding of an antibody (e.g., a VHH antibody) to a target molecule, the term “specific binding,” “specifically binds,” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target (e.g., IL23R) means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term “specific binding,” “specifically binds,” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a KD for the target of 10'4M or lower, alternatively 10'5M or lower, alternatively 106M or lower, alternatively 107M or lower, alternatively 108M or lower, alternatively 109M or lower, alternatively 1010M or lower, alternatively 1011M or lower, alternatively 10’12M or lower or a KD in the range of 104M to 106M or 106M to 1010M or 107M to 109M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In one embodiment, the term “specific binding,” or a variant thereof, refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.The term “inflammatory bowel disorder,” “inflammatory bowel disease” or IBD is used herein in the broadest sense and includes all diseases and pathological conditions the pathogenesis of which involves recurrent inflammation in the intestine, including small intestine and colon. Commonly seen IBD includes ulcerative colitis and Crohn’s disease. IBD is not limited to UC and CD. The manifestations of the disease include but are not limited to inflammation and a decrease in epithelial integrity in the intestine.The term “irritable bowel syndrome” or “IBS” is used herein in the broadest sense and includes idiopathic bowel disorders with symptoms including abdominal pain and changes in bowel movements (e.g., diarrhea or constipation). IBS can be classified as IBS with predominant constipation (IBS-C), IBS with predominant diarrhea (IBS-D), IBS with mixed bowel habits (IBS-M), or IBS unclassified (IBS-U).The term “pathogenic inflammation” used herein in the context of a Gl-related disease refers to acute or chronic inflammation of the Gl tract or accessory organs of digestion (e.g., mouth, esophagus, stomach, small intestine, gallbladder, pancreas, appendix, large intestine, rectum, anus, or liver). Pathogenic inflammation of the Gl tract or accessory organs can include tonsillitis, pharyngitis, esophagitis, gastroenteritis, cholecystitis, pancreatitis, or appendicitis.The term “gut-associated infection” used herein refers to any infection of the Gl tract or accessory organs of digestion (e.g., mouth, esophagus, stomach, small intestine, gallbladder, pancreas, appendix, large intestine, rectum, anus, or liver). A gut-assiciated infection can be, for example, viral, bacterial, or parasitic. A gut-associated infection can be, for example, a Salmonella (e.g., S. typhior S. paratyphi), Clostridium difficile, Vibrio, Shigella, Clostridium, Campylobacter, Staphylococcus, Giardia, Entamoeba, Cryptosporidium, rotavirus, norovirus, adenovirus, astrovirus, or helminth infection.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.For example, with respect to a Gl-related disease (e.g., inflammatory bowel disease (IBD), e.g., ulcerative colitis or Crohn’s disease, and various Gl cancers), “treatment” can refer to a decrease in the likelihood of developing a Gl-related disease, a decrease in the rate of developing a Gl-related disease, and / or a decrease in the severity of a Gl-related disease. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviating symptoms, diminishing any direct or indirect pathological consequences of the disease, preventing the disease, decreasing the rate of disease progression, ameliorating or palliating the disease state, and causing remission or improved prognosis.The "pathology" of a disease or condition includes all phenomena that compromise the well-being of the subject. In the case of a Gl-related disease, this includes, without limitation, ulcers, inflammation of the digestive tract, diarrhea, abdominal pain, fatigue, weight loss, fever, vomiting, abscesses, and formation of fistulas."Alleviation", “alleviating” or equivalents thereof, refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to ameliorate, prevent, slow down (lessen), decrease or inhibit a disease or condition, e.g., a Gl-related disease (e.g., inflammatory bowel disease (IBD), e.g., ulcerative colitis or Crohn’s disease, and various Gl cancers). Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in whom the disease or condition is to be prevented."Chronic" administration refers to administration of an agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect for an extended period of time.“Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.“Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, forPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program."Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995)."Stringent conditions" or "high stringency conditions", as defined herein, can be identified by those that: (1 ) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride / 0.0015 M sodium citrate / 0.1 % sodium dodecyl sulfate at 5OC; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v / v) formamide with 0.1 % bovine serum albumin / 0.1% Ficoll / 0.1 % polyvinylpyrrolidone / 50mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) overnight hybridization in a solution that employsPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-150% formamide, 5 x SSC (0.75 M NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 pg / ml), 0.1% SDS, and 10% dextran sulfate at 42°C, with a 10 minute wash at 42°C in 0.2 x SSC (sodium chloride / sodium citrate) followed by a 10 minute high-stringency wash consisting of 0.1 x SSC containing EDTA at 55°C."Moderately stringent conditions" can be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength, and %SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37°C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCI, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg / ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37-50°C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.The term "pharmaceutical formulation" or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, diluent, stabilizer, or preservative.The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of a heavy chain and a light chain (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6thed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."III. COMPOSITIONS AND METHODSAs previously mentioned, disclosed herein are improved antibodies that bind to IL23R. The VHH antibodies provided herein have advantageous properties, including high affinity for both human and cynomolgus monkey (cyno) IL23R, the ability to inhibit binding of IL23 to IL23R, stability at low pH,PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 resistance to proteolysis (e.g., resistance to proteolysis by elastase, trypsin, chymotrypsin, or pancreatin), the ability to evade binding by pre-existing anti-VHH antibodies, and the ability to treat IL23-mediated diseases and disorders, such as, e.g., Gl-related IL23-mediated diseases and disorders (e.g., inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn’s disease (CD)), colon cancer, small intestine cancer, gastric cancer, irritable bowel syndrome, gastrointestinal ulcer, gut-associated infections (e.g., a Salmonella infection or a Clostridium difficile infection), celiac disease, or pathogenic inflammation). For example, the VHH antibodies provided herein also bind to human and cyno IL23R with high affinity, e.g., as assessed using surface plasmon resonance (SPR). For example, the VHH antibodies disclosed herein may lack protease cleavage sites (e.g., an elastase, trypsin, or chymotrypsin sites) or have amino acid changes that inhibit or disrupt protease cleavage (e.g., a glutamine or an aspartic acid residue at the P1 ' position of at least one chymotrypsin cleavage site, a phenylalanine or a glycine residue at the P1 position of at least one trypsin cleavage site, or a proline residue at the P1 ' position of at least one trypsin cleavage site). The VHH antibodies disclosed herein may not be significantly bound by any pre-existing anti-VHH antibodies in a subject (e.g., a human). The VHH antibodies disclosed herein can be used for treating IL23-mediated diseases and disorders (e.g., Gl- related disease). The unexpectedly favorable properties described above (e.g., resistance to proteolysis (e.g., resistance to proteolysis by elastase, trypsin, chymotrypsin, or pancreatin) and ability to evade binding by pre-existing anti-VHH antibodies) are particularly advantageous in the context of oral administration, e.g., for treatment of IL23-mediated diseases and disorders (e.g., Gl-related disease (e.g., IBD (e.g., UC or CD) and various Gl cancers)). For example, a pharmaceutical composition containing an anti-IL23R VHH antibody described herein can be orally administered to treat a subject with an IL23- mediated disease or disorder (e.g., a Gl-related disease (e.g., IBD, e.g., UC or CD, and various Gl cancers)). In this example, the anti-IL23R VHH antibody can resist proteolysis by proteases in the Gl tract (e.g., trypsin, chymotrypsin, and elastase), traverse the intestinal barrier, evade binding by pre-existing anti-VHH antibodies, and bind to IL23R present on immune cells (e.g., T cells (e.g., T helper 17 (Th17) cells) and type 3 innate lymphoid cells (ILC3s)), thereby inhibiting binding of IL23 to IL23R and inhibiting IL23R signaling (e.g., reducing phosphorylation of STAT3). The inhibition of IL23R signaling can inhibit the production of proinflammatory cytokines (e.g., IL22 and IL17) and result in a decrease in pathogenic inflammation, thereby treating Gl-related disease.A. Exemplary Anti-IL23R VHH AntibodiesIn one example, provided herein is an anti-IL23R VHH antibody that includes a binding domain including at least one, two, or all three complementarity-determining regions (CDRs) selected from: (a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1 ), wherein Xi is A or S; (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2 is G or D; and (c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2is D or G, X3is Q, S, or D, and X4is T or V; or a combination of one or more of the above CDRs and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 1 -8. For instance,PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 the anti-IL23R VHH antibody may include a binding domain including at least one, two, or all three CDRs selected from: (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR- H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1G (SEQ ID NO: 5), wherein Xi is V or T; and (c) a CDR-H3 comprising the amino acid sequence of KRPX1AGWX2TYDY (SEQ ID NO: 6), wherein Xi is D or G, and X2 is Q, S, or D. For example, the anti-IL23R VHH antibody includes a binding domain including at least one, two, or all three CDRs selected from: (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8) (e.g., an anti-IL23R VHH antibody including a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8)).In another example, provided herein is an anti-IL23R VHH antibody that contains a binding domain comprising an amino acid sequence having at least about 80% sequence identity (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMAWFRQAPGKEREFVAESWSSGTTYYGASVVGRFT MSRDDSKNTVYLQMNSLRAEDTAVYYCAAKRPDAGWQTYDYWGQGTLVQVQSA (SEQ ID NO: 9). For example, in some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 85% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 95% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 96% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 97% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 98% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 9. For example, in some instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence including the amino acid sequence of SEQ ID NO: 9. In yet other instances, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 9.In another example, provided herein is an anti-IL23R VHH antibody having a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domainPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 comprises an amino acid sequence having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMAWFRQAPGKEREFVAESWSSGTTYYGASVVGRFT MSRDDSKNTVYLQMNSLRAEDTAVYYCAAKRPDAGWQTYDYWGQGTLVQVQSA (SEQ ID NO: 9). In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 85% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 95% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 96% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 97% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 98% sequence identity to the amino acid sequence of SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 9.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4) or an amino acid sequence with one, two, or three addition, substitution, and / or deletion mutations compared to SEQ ID NO: 4; (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7) or an amino acid sequence with one, two, or three addition, substitution, and / or deletion mutations compared to SEQ ID NO: 7; and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8) or an amino acid sequence with one, two, or three addition, substitution, and / or deletion mutations compared to SEQ ID NO: 8. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having no more than six addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having six addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having five addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having four addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having three addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having two addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. In some instances, the anti-IL23R VHH antibody has a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence ofPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1KRPDAGWQTYDY (SEQ ID NO: 8), wherein the binding domain comprises an amino acid sequence having one addition, substitution, and / or deletion mutation compared to SEQ ID NO: 9. In another example, provided herein is an anti-IL23R VHH antibody that contains a binding domain comprising an amino acid sequence having no more than 25 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, or 25) addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9. For example, the anti-IL23R VHH antibody contains a binding domain comprising an amino acid sequence having no more than six addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9.Any of the anti-IL23R VHH antibodies provided herein may include one, two, three, or four of the following framework regions (FRs): (a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQX1GX2SLRLSCAASGX3TFS (SEQ ID NO: 10), wherein Xi is P or L, X2is G or D, and X3 is F, G, Y, or R; (b) an FR-2 comprising the amino acid sequence of WFRQAPGKEREFVA (SEQ ID NO: 1 1 ); (c) an FR-3 comprising the amino acid sequence of RFTX1SRDDX2KNTVYLQMNSLX3X4EDTAVYYCAA (SEQ ID NO: 12), wherein Xi is M or I, X2is S or A, X3 is R or K, and X4 is A or P; and (d) an FR-4 comprising the amino acid sequence of WGQGTLVX1VX2S (SEQ ID NO: 13), wherein Xi is Q or T and X2 is Q or S; or a combination of one or more of the above FRs and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 10-13. For example, the anti-IL23R VHH antibody includes at least one, two, three, or four of the following FRs: (a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 14); (b) an FR-2 comprising the amino acid sequence of SEQ ID NO: 1 1 ; (c) an FR-3 comprising the amino acid sequence of RFTMSRDDSKNTVYLQMNSLRAEDTAVYYCAA (SEQ ID NO: 15); and (d) an FR-4 comprising the amino acid sequence of WGQGTLVQVQS (SEQ ID NO: 16).Any of the anti-IL23R VHH antibodies provided herein may include one, two, or three of the following: a Q at position 1 10, a Q at position 1 12, and an A at position 1 14 (Kabat numbering). In some instances, anti-IL23R VHH antibodies provided herein may include a Q at position 1 10, a Q at position 1 12, and an A at position 1 14 (Kabat numbering). In some instances, the modification can be a T1 10Q substitution, a S1 12Q substition, and an A1 14 addition (Kabat numbering). In some instances, a Q at position 1 10, a Q at position 1 12, and an A at position 1 14 can decrease or eliminate binding by preexisting anti-VHH antibodies to the anti-IL23R VHH antibody having such a modification. In some instances, anti-IL23R VHH antibodies provided herein with a Q at position 1 10, a Q at position 1 12, and an A at position 1 14 can evade pre-existing anti-VHH antibodies in a subject (e.g., a human).Any of the antibodies provided herein may specifically bind human or cynomolgus monkey (cyno) IL23R. In some instances, the antibody specifically binds both human and cyno IL23R. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a Ko of 100 nM or lower (e.g., 100 nM or lower, 10 nM or lower, 1 nM or lower, 100 pM or lower, 10 pM or lower, 1 pM or lower, 0.1 pM or lower, 100 fM or lower, or 10 fM or lower). In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD of about 1 nM or lower (e.g., about 1 nM or lower, 100 pM or lower, 10 pM or lower, 1 pM or lower, or 0.1 pMPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 or lower). In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD between about 100 fM and about 1 nM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD between about 750 fM and about 300 pM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD between about 1 pM and about 200 pM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD between about 50 pM and about 80 pM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds human IL23R with a KD of about 74 pM. In certain instances, an anti-IL23R VHH antibody provided herein specifically binds cyno IL23R with a KD of about 58 pM. For example, in some instances, the antibody specifically binds both human and cyno IL23R with a KD of between about 1 pM and about 1 nM (e.g., between about 1 pM and about 900 pM, between about 1 pM and about 800 pM, between about 1 pM and about 700 pM, between about 1 pM and about 600 pM, between about 1 pM and about 500 pM, between about 1 pM and about 400 pM, between about 1 pM and about 300 pM, between about 1 pM and about 200 pM, between about 1 pM and about 190 pM, between about 1 pM and about 180 pM, between about 1 pM and about 170 pM, between about 1 pM and about 160 pM, between about 1 pM and about 150 pM, between about 1 pM and about 140 pM, between about 1 pM and about 130 pM, between about 1 pM and about 120 pM, between about 1 pM and about 110 pM, between about 1 pM and about 100 pM, between about 1 pM and about 90 pM, between about 1 pM and about 80 pM, between about 1 pM and about 70 pM, between about 1 pM and about 60 pM, between about 1 pM and about 50 pM, between about 1 pM and about 40 pM, between about 1 pM and about 30 pM, between about 1 pM and about 20 pM, or between about 1 pM and about 10 pM). In some instances, the antibody specifically binds both human and cyno IL23R with a KD of between about 1 pM and about 250 pM (e.g., between about 1 pM and about 250 pM, between about 1 pM and about 225 pM, between about 1 pM and about 200 pM, between about 1 pM and about 190 pM, between about 1 pM and about 180 pM, between about 1 pM and about 170 pM, between about 1 pM and about 160 pM, between about 1 pM and about 150 pM, between about 1 pM and about 140 pM, between about 1 pM and about 130 pM, between about 1 pM and about 120 pM, between about 1 pM and about 110 pM, between about 1 pM and about 100 pM, between about 1 pM and about 90 pM, between about 1 pM and about 80 pM, between about 1 pM and about 70 pM, between about 1 pM and about 60 pM, between about 1 pM and about 50 pM, between about 1 pM and about 40 pM, between about 1 pM and about 30 pM, between about 1 pM and about 20 pM, or between about 1 pM and about 10 pM). In some instances, the antibody specifically binds both human and cyno IL23R with a KD of between about 50 pM and about 80 pM (e.g., about 50 pM, about 55 pM, about 60 pM, about 65 pM, about 70 pM, about 75 pM, or about 80 pM). In certain instances, an anti-IL23R VHH antibody provided herein specifically binds both human and cyno IL23R with a KD of about 60 pM. In some instances, an anti-IL23R VHH antibody provided herein specifically binds human IL23R with a KD of about 74 pM. In some instances, an anti-IL23R VHH antibody provided herein specifically binds cyno IL23R with a KD of about 58 pM. Any of the preceding KD values may be determined by surface plasmon resonance, for example, as described herein (see, e.g., Example 2). In some instances, any of the preceding KDPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 values may be determined by surface plasmon resonance carried out on the BIACORE® T200 (GE Healthcare) at about 37°C using HBS-P+ (GE Healthcare) running buffer.In another example, an anti-IL23R VHH antibody provided herein is capable of inhibiting the binding of IL23 to IL23R. In some instances, the inhibiting is determined by a cell-based functional assay, such as the cell-based assay described in Example 2 herein.In another example, an anti-IL23R VHH antibody provided herein inhibits the binding of IL23 to IL23R. In some instances, the inhibiting is determined by a cell-based functional assay, such as the cellbased assay described in Example 2 herein.In another example, an anti-IL23R VHH antibody provided herein is at least partially resistant to proteolysis by one or more proteases (e.g., elastase, trypsin, or chymotrypsin). In some instances, the anti-IL23R VHH antibody provided herein is at least partially resistant to proteolysis by one or more of elastase, trypsin, chymotrypsin, or pancreatin. In some instances, the anti-IL23R VHH antibody provided herein is resistant to proteolysis by one or more of elastase, trypsin, chymotrypsin, pancreatin. In some instances, resistance to proteolysis is determined by an in vitro assay at 37°C, for example, an in vitro proteolysis assay as described in Example 1 herein. In some instances, the in vitro proteolysis assay is performed with between about 0.1 pg to about 100 pg (e.g., between about 0.2 pg to about 100 pg, e.g., between about 0.5 pg to about 100 pg, e.g., between about 0.5 pg to about 90 pg, e.g., between about 1 pg to about 80 pg, e.g., between about 1 pg to about 70 pg, e.g., between about 1 pg to about 60 pg, e.g., between about 1 pg to about 50 pg, e.g., between about 1 pg to about 40 pg, e.g., between about 1 pg to about 30 pg, e.g., about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 6 pg, about 7 pg, about 8 pg, about 9 pg, about 10 pg, about 12 pg, about 13 pg, about 14 pg, about 15 pg, about 16 pg, about 17 pg, about 18 pg, about 19 pg, about 20 pg, about 21 pg, about 22 pg, about 23 pg, about 24 pg, about 25 pg, about 26 pg, about 27 pg, about 28 pg, about 29 pg, or about 30 pg) of the anti-IL23R VHH antibody provided herein. In some instances, the in vitro proteolysis assay is performed with about 10 pg (e.g., about 10 pg ± 1 pg, e.g., about 10 pg ± 0.5 pg, e.g., about 10 pg ± 0.2 pg, e.g., about 10 pg ± 0.1 pg, e.g., about 10 pg) of the anti-IL23R VHH antibody provided herein. In some instances, the in vitro proteolysis assay is performed with about 15 pg (e.g., about 15 pg ± 1 pg, e.g., about 15 pg ± 0.5 pg, e.g., about 15 pg ± 0.2 pg, e.g., about 15 pg ± 0.1 pg, e.g., about 15 pg) of the anti-IL23R VHH antibody provided herein. In some instances, the in vitro proteolysis assay is performed with between about 1 pg / mL to about 1000 pg / mL (e.g., between about 10 pg / mL to about 950 pg / mL, e.g., between about 50 pg / mL to about 900 pg / mL, e.g., between about 100 pg / mL to about 850 pg / mL, e.g., between about 150 pg / mL to about 800 pg / mL, e.g., between about 200 pg / mL to about 750 pg / mL, e.g., between about 250 pg / mL to about 700 pg / mL, e.g., between about 300 pg / mL to about 650 pg / mL, e.g., between about 350 pg / mL to about 600 pg / mL, e.g., between about 400 pg / mL to about 600 pg / mL, e.g., between about 410 pg / mL to about 590 pg / mL, e.g., between about 420 pg / mL to about 580 pg / mL, e.g., between about 430 pg / mL to about 570 pg / mL, e.g., between about 440 pg / mL to about 560 pg / mL, e.g., between about 450 pg / mL to about 550 pg / mL, e.g., between about 460 pg / mL to about 540 pg / mL, e.g., between about 470 pg / mL to about 530 pg / mL, e.g., between about 480 pg / mL to about 520 pg / mL, e.g., between about 490 pg / mL to about 510 pg / mL, e.g., between about 495 pg / mL to about 505 pg / mL, e.g., about 495 pg / mL, about 496 pg / mL, about 497 pg / mL, about 498 pg / mL, about 499 pg / mL, about 500 pg / mL, about 501PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 gg / mL, about 502 gg / mL, about 503 gg / mL, about 504 gg / mL, or about 505 gg / mL) of trypsin. In some instances, the in vitro proteolysis assay is performed with about 500 gg / mL (e.g., about 500 gg / mL ± 5 gg / mL, e.g., about 500 gg / mL ± 4 gg / mL, e.g., about 500 gg / mL ± 3 gg / mL, e.g., about 500 gg / mL ± 2 gg / mL, e.g., about 500 gg / mL ± 1 gg / mL, e.g., about 500 gg / mL ± 0.5 gg / mL, e.g., about 500 gg / mL) of trypsin. In some instances, the in vitro proteolysis assay is performed with between about 1 gg / mL to about 1000 gg / mL (e.g., between about 1 gg / mL to about 950 gg / mL, e.g., between about 5 gg / mL to about 900 gg / mL, e.g., between about 10 gg / mL to about 850 gg / mL, e.g., between about 15 gg / mL to about 800 gg / mL, e.g., between about 20 gg / mL to about 750 gg / mL, e.g., between about 25 gg / mL to about 700 gg / mL, e.g., between about 30 gg / mL to about 650 gg / mL, e.g., between about 35 gg / mL to about 600 gg / mL, e.g., between about 40 gg / mL to about 550 gg / mL, e.g., between about 45 gg / mL to about 500 gg / mL, e.g., between about 50 gg / mL to about 450 gg / mL, e.g., between about 55 gg / mL to about 400 gg / mL, e.g., between about 60 gg / mL to about 350 gg / mL, e.g., between about 65 gg / mL to about 300 gg / mL, e.g., between about 70 gg / mL to about 250 gg / mL, e.g., between about 75 gg / mL to about 200 gg / mL, e.g., between about 80 gg / mL to about 150 gg / mL, e.g., between about 80 gg / mL to about 140 gg / mL, e.g., between about 80 gg / mL to about 130 gg / mL, e.g., between about 80 gg / mL to about 120 gg / mL, e.g., between about 85 gg / mL to about 1 15 gg / mL, e.g., between about 90 gg / mL to about 110 gg / mL, e.g., about 90 gg / mL, about 91 gg / mL, about 92 gg / mL, about 93 gg / mL, about 94 gg / mL, about 95 gg / mL, about 96 gg / mL, about 97 gg / mL, about 98 gg / mL, about 99 gg / mL, about 100 gg / mL, about 101 gg / mL, about 102 gg / mL, about 103 gg / mL, about 104 gg / mL, about 105 gg / mL, about 106 gg / mL, about 107 gg / mL, about 108 gg / mL, about 109 gg / mL, about 110 gg / mL) of chymotrypsin. In some instances, the in vitro proteolysis assay is performed with about 100 gg / mL (e.g., about 100 gg / mL ± 5 gg / mL, e.g., about 100 gg / mL ± 4 gg / mL, e.g., about 100 gg / mL ± 3 gg / mL, e.g., about 100 gg / mL ± 2 gg / mL, e.g., about 100 gg / mL ± 1 gg / mL, e.g., about 100 gg / mL ± 0.5 gg / mL, e.g., about 100 gg / mL) of chymotrypsin. In some instances, the in vitro proteolysis assay is performed with between about 10 gg / mL to about 10000 gg / mL (e.g., between about 10 gg / mL to about 9000 gg / mL, e.g., between about 100 gg / mL to about 9000 gg / mL, e.g., between about 200 gg / mL to about 8000 gg / mL, e.g., between about 300 gg / mL to about 7500 gg / mL, e.g., between about 400 gg / mL to about 7000 gg / mL, e.g., between about 500 gg / mL to about 6000 gg / mL, e.g., between about 500 gg / mL to about 5000 gg / mL, e.g., between about 600 gg / mL to about 4000 gg / mL, e.g., between about 700 gg / mL to about 3000 gg / mL, e.g., between about 800 gg / mL to about 2000 gg / mL, e.g., between about 850 gg / mL to about 1500 gg / mL, e.g., between about 900 gg / mL to about 1200 gg / mL, e.g., between about 910 gg / mL to about 1100 gg / mL, e.g., between about 920 gg / mL to about 1090 gg / mL, e.g., between about 930 gg / mL to about 1080 gg / mL, e.g., between about 940 gg / mL to about 1070 gg / mL, e.g., between about 950 gg / mL to about 1060 gg / mL, e.g., between about 960 gg / mL to about 1050 gg / mL, e.g., between about 970 gg / mL to about 1040 gg / mL, e.g., between about 975 gg / mL to about 1030 gg / mL, e.g., between about 980 gg / mL to about 1020 gg / mL, e.g., between about 990 gg / mL to about 1010 gg / mL, e.g., between about 995 gg / mL to about 1005 gg / mL, e.g., about 995 gg / mL, about 996 gg / mL, about 997 gg / mL, about 998 gg / mL, about 999 gg / mL, about 1000 gg / mL, about 1001 gg / mL, about 1002 gg / mL, about 1003 gg / mL, about 1004 gg / mL, about 1005 gg / mL) of elastase. In some instances, the in vitro proteolysis assay is performed with about 1000 gg / mL (e.g., about 1000 gg / mL ± 10 gg / mL, e.g., aboutPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-11000 pg / mL ± 5 pg / mL, e.g., about 1000 pg / mL ± 4 pg / mL, e.g., about 1000 pg / mL ± 3 pg / mL, e.g., about1000 pg / mL ± 2 pg / mL, e.g., about 1000 pg / mL ± 1 pg / mL, e.g., about 1000 gg / mL ± 0.5 gg / mL, e.g., about 1000 pg / mL) of elastase. In some instances, the in vitro proteolysis assay is performed with with between about 0.001 gg / mL to about 1000 mg / mL (e.g., between about 0.01 gg / mL to about 1000 mg / mL, e.g., between about 0.1 gg / mL to about 1000 mg / mL, e.g., between about 1 gg / mL to about 1000 mg / mL, e.g., between about 10 pg / mL to about 1000 mg / mL, e.g., between about 0.05 mg / mL to about1000 mg / mL, e.g., between about 0.1 mg / mL to about 900 mg / mL, e.g., between about 0.1 mg / mL to about 800 mg / mL, e.g., between about 0.1 mg / mL to about 700 mg / mL, e.g., between about 0.1 mg / mL to about 600 mg / mL, e.g., between about 0.1 mg / mL to about 500 mg / mL, e.g., between about 0.1 mg / mL to about 400 mg / mL, e.g., between about 0.1 mg / mL to about 300 mg / mL, e.g., between about 0.1 mg / mL to about 200 mg / mL, e.g., between about 0.1 mg / mL to about 100 mg / mL, e.g., between about 0.5 mg / mL to about 50 mg / mL, e.g., between about 0.7 mg / mL to about 40 mg / mL, e.g., between about 0.8 mg / mL to about 30 mg / mL, e.g., between about 0.9 mg / mL to about 25 mg / mL, e.g., between about 1 mg / mL to about 20 mg / mL, e.g., between about 5 mg / mL to about 15 mg / mL, e.g., about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 1 1 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL) of pancreatin. In some instances, the in vitro proteolysis assay is performed with up to about 10 mg / mL (e.g., up to about 10 mg / mL ± 2 mg / mL, e.g., up to about 10 mg / mL ± 1 mg / mL, e.g., up to about 10 mg / mL ± 0.5 mg / mL, e.g., up to about 10 mg / mL ± 0.1 mg / mL, up to about 10 mg / mL) of pancreatin. In some instances, the in vitro proteolysis assay is performed with about 10 mg / mL (e.g., about 10 mg / mL ± 2 mg / mL, e.g., about 10 mg / mL ± 1 mg / mL, e.g., about 10 mg / mL ± 0.5 mg / mL, e.g., about 10 mg / mL ± 0.1 mg / mL, about 10 mg / mL) of pancreatin. In some instances, at least about 5% (e.g., at least about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100%) of the anti-IL23R VHH antibody provided herein is intact after at least about one hour of exposure to elastase, trypsin, chymotrypsin, or pancreatin. In some instances, at least about 5% (e.g., at least about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100%) of the anti-IL23R VHH antibody provided herein is intact after at least about three hours of exposure to elastase, trypsin, chymotrypsin, or pancreatin. In some instances, at least about 50% (e.g., at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) of the anti-IL23R VHH antibody provided herein is intact after at least about four hours of exposure to trypsin, chymotrypsin, or pancreatin. In some instances, at least about 50% (e.g., at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) of the anti-IL23R VHH antibody provided herein is intact after at least about three hours of exposure to elastase. In some instances, at least about 50% (e.g., at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) of the anti-IL23R VHH antibody provided herein is intact after at least about 20 hours of exposure to pancreatin.Any of the anti-IL23R VHH antibodies provided herein may be a chimeric or humanized antibody. Any of the anti-IL23R VHH antibodies provided herein may be a full-length antibody.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1Any of the anti-IL23R VHH antibodies provided herein may be an antibody fragment that binds IL23R.Any of the anti-IL23R VHH antibodies provided herein may be a single-domain antibody.Any of the anti-IL23R VHH antibodies provided herein may bind IL23R.Any of the anti-IL23R VHH antibodies provided herein may not be significantly bound by any preexisting anti-VHH antibodies in a subject (e.g., a human). In some instances, the anti-IL23R VHH antibodies provided herein can evade pre-existing anti-VHH antibodies in a human. Anti-IL23R VHH antibodies having such mutations can minimize or avoid an undesirable anti-drug antibody (ADA) response in the subject (e.g., human).Any of the anti-IL23R VHH antibodies provided herein may be an immunoconjugate. In some instances, the anti-IL23R VHH antibodies provided herein may be conjugated to one or more heterologous molecule(s) (e.g., a therapeutic molecule (e.g., chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof)) or a molecule used for detection (e.g., radioactive isotopes (e.g., zirconium 89), fluorophores, enzymes (e.g., horseradish peroxidase or luciferase))). For example, the heterologous molecule can be a therapeutic molecule (e.g., chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof)). In another example, the heterologous molecule is a molecule used for detection (e.g., radioactive isotopes (e.g., zirconium 89), fluorophores, or enzymes (e.g., horseradish peroxidase or luciferase).Any of the anti-IL23R VHH antibodies provided herein may be a monospecific antibody. In other instances, any of the anti-IL23R VHH antibodies provided herein may be a multispecific antibody (e.g., a bispecific antibody). In some instances, the bispecific antibody comprises a second binding domain that binds to a second biological molecule.Any of the anti-IL23R VHH antibodies provided herein may be encoded by an isolated nucleic acid. For example, a vector may contain the isolated nucleic acid; the vector can be an expression vector, wherein the isolated nucleic acid is expressed under suitable conditions. In some instances, a host cell may contain the vector. In certain instances, the host cell is a eukaryotic cell, such as a mammalian cell. In a particular instance, the mammalian cell is a Chinese hamster ovary (CHO) cell. In another instance, the host cell is a prokaryotic cell, such as E. coli.In a further aspect, any of the anti-IL23R VHH antibodies disclosed herein may incorporate any of the features, singly or in combination, as described in Sections 1 -8 below:1. Antibody AffinityAn antibody provided herein may have a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, < 1 pM, or < 0.1 pM (e.g., 106M or less, e.g., from 106M to 109M or less, e.g., from 109M to 1013M or less).In some instances, KD is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc.) is performed at 25°C with immobilized antigen CM5 chips at ~10 response units (RU). Carboxymethylated dextran biosensorPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 chips (CM5, BIACORE, Inc.) may be activated with A / -ethyl-A / - (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and A / -hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg / ml (~0.2 pM) before injection at a flow rate of 5 pL / minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of VHH (0.78 nM to 500 nM) are injected in phosphate buffered saline (PBS) with 0.05% polysorbate 20 (TWEEN®-20) surfactant (PBST) at 25°C at a flow rate of approximately 25 pL / min. Association rates (kon) and dissociation rates (kotf) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio kow / kon. See, for example, Chen et al. (J. Mol. Biol. 293:865-881 , 1999). If the on-rate exceeds 106M’1s1by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25°C of a 20 nM anti-antigen antibody (VHH form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM- AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.In some instances, KD is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using a BIACORE®T200 (GE Healthcare) at 37°C using HBS-P+ (GE Healthcare) running buffer. In a particular example, 1 .5 pg / mL of IL23R-Fc is captured using an anti-HulgG1 Fc capture kit (GE Healthcare) and monomeric VHHs are added as the analyte in solution at a flow rate of 30 pL / min. The VHH may be titrated using a dilution series from 100-0 nM. In some examples, sensorgrams are fit to a 1 :1 Langmuir model to identify kinetic parameters.In some instances, KD is measured by a radiolabeled antigen binding assay (RIA). For example, an RIA is performed with the VHH version of an antibody of interest and its antigen. In one non-limiting example, solution binding affinity of VHHs for antigen is measured by equilibrating VHH with a minimal concentration of (125l)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-VHH antibody-coated plate. To establish conditions for the assay, MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 pg / mL of a capturing anti-VHH antibody in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w / v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In a nonadsorbent plate (NUNC™ #269620), 100 pM or 26 pM [125l]-antigen are mixed with serial dilutions of a VHH of interest. The VHH of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN®-20) in PBS. When the plates have dried, 150 pL / well of scintillant (MICRGSCINT-20™; Packard) is added, and the plates are counted on a TOPCOUNT™ gamma counter (Packard) for ten minutes. Concentrations of each VHH that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-12. Antibody FragmentsAny of the antibodies provided herein may be an antibody fragment (e.g., an antigen-binding (e.g., I L23R-binding) antibody fragment). Antibody fragments include, but are not limited to, VHHs, singledomain antibodies, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see U.S. Patent No. 5,641 ,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062

[1995] ); single-chain antibody molecules; multispecific antibodies formed from antibody fragments; and other fragments described below. In certain instances, the antibody fragment is a VHH. In certain instances, the antibody fragment is a Fab. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 1 13, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93 / 16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01 161 ; Hudson et al. Nat. Med. 9:129-134, 2003; and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448, 1993. Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134, 2003.Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain instances, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1 ). In certain instances, a single-domain antibody includes antibody variable domains from a camelid (e.g., a dromedary, a camel, a llama, or an alpaca), shark (e.g., a Ginglymostomatidae shark), or rodent (e.g., a mouse or rat). In some instances , a single-domain antibody is a VHH.Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or CHO cells), as described herein.Any of the above antibody fragments may be humanized. In certain instances, an antibody fragment may be modified to reduce protease sensitivity (e.g., sensitivity to cleavage by elastase, trypsin, chymotrypsin, or pancreatin), reduce binding by anti-drug antibodies (e.g., pre-existing anti-VHH antibodies), be amenable to conjugation, reduce aggregation, or increase stability.3. Antibody FusionsAny of the VHH antibodies provided herein may be an antibody fusion (e.g., an antigen-binding (e.g., IL23R-binding) fusion antibody). The VHH antibodies provided herein may be adapted or modified by fusion to increase the half-life of the VHH antibody in serum. An Fc region of an antibody or an antiserum albumin antibody or fragment thereof, for example, may be fused to any of the VHH antibodies provided herein. Such antibody fusions may result in half-life extension of the antibody in the serum.In some instances, VHH antibodies may be an antibody fusion comprising an immunoglobulin Fc region or functional part thereof of an immunoglobulin heavy chain, such that the VHH antibody is a full- length antibody, e.g., a full-length antibody in which each amino terminus of the Fc region is fused to thePATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 carboxy terminus of the binding domain of a VHH antibody provided herein. The Fc region or functional fragment thereof may be derived from IgG, IgM, IgD, IgA or IgE isotypes. The Fc region or functional fragment thereof may be derived from IgG 1 , lgG2, lgG3, or lgG4 subclasses. The Fc region or fragment thereof may be a human Fc region or fragment thereof. In some instances, the Fc region or fragment thereof may be a camelid Fc region or fragment thereof, for example a llama Fc region or fragment thereof. The camelid Fc region or fragment thereof may be humanized. In some examples, the C-terminal end of the antibody or antigen-binding fragment (e.g., a VHH antibody) may be linked or fused to the N- terminal end of the Fc region. In other examples, the N-terminal end of the Fc region may be linked or fused to the C-terminal end of the antibody or antigen-binding fragment (e.g., a VHH antibody). These linking modes can be extended in order to link additional antibody fragments for generating tri-, tetra-, etc. functional constructs.In some instances, a VHH antibody is connected to an Fc region or functional fragment thereof via a hinge region. For example, a hinge region of a camelid or human immunoglobulin heavy chain molecules from IgG 1 , lgG2, lgG3, lgG4, IgM, IgD, IgA or IgE may be used in a VHH-Fc fusion antibody or protein. The hinge region of a camelid immunoglobulin heavy chain molecule may be humanized.Additionally, an antibody fusion provided herein may comprise a VHH antibody disclosed herein and an anti-serum protein antibody or antibody fragment. The serum protein may be any suitable protein found in the serum of the subject. Exemplary serum proteins include serum albumin, serum immunoglobulins, thyroxine-binding protein, transferrin, fibrinogen. For example, a VHH antibody may be linked or fused to a human anti-serum albumin antibody or fragment thereof. Such a fusion may increase the serum half-life of the VHH antibody or improve targeting or compartmentalization as compared to a VHH antibody that is not fused to an anti-serum protein antibody or antibody fragment such as an antiserum albumin antibody.4. Chimeric and Humanized AntibodiesAn antibody provided herein may be a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81 :6851 - 6855, 1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a camel, llama, vicuna, dromedary, alpaca, guanaco, mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.In some instances , a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. Some FR residues in a humanized antibody may be substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), for example, to restore or improve antibody specificity or affinity.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Humanized antibodies and methods of making them are reviewed, for example, in Almagro et al. Front. Biosci. 13:1619-1633, 2008, and are further described, e.g., in Riechmann et al. Nature 332:323- 329, 1988; Queen et al. Proc. Natl. Acad. Sci. USA 86:10029-10033, 1989; US Patent Nos. 5, 821 ,337, 7,527,791 , 6,982,321 , and 7,087,409; Kashmiri et al. Methods 36:25-34, 2005 (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498, 1991 (describing “resurfacing”); Dall’Acqua et al. Methods 36:43-60, 2005 (describing “FR shuffling”); and Osbourn et al. Methods 36 6 - 68, 2005 and Klimka et al. Br. J. Cancer, 83:252-260, 2000 (describing the “guided selection” approach to FR shuffling).Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151 :2296, 1993); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285, 1992; and Presta et al. J. Immunol., 151 :2623, 1993); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro et al. Front. Biosci. 13:1619-1633, 2008); and framework regions derived from screening FR libraries (see, e.g., Baca et al. J. Biol. Chem. 272:10678-10684, 1997 and Rosok et al. J. Biol. Chem. 271 :22611 -22618, 1996).5. Human AntibodiesAn antibody provided herein may be a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk et al. Curr. Opin. Pharmacol. 5:368-74, 2001 and Lonberg, Curr. Opin. Immunol. 20:450-459, 2008.Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1 125, 2005. See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041 ,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007 / 0061900, describing VELOCIMOUSE® technology. Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001 , 1984; Brodeur et al. Monoclonal Antibody Production Techniques and Applications, pp. 51 -63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. J. Immunol. 147: 86, 1991). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al. Proc. Natl. Acad. Sci. USA, 103:3557-3562, 2006. Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonalPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268, 2006 (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers et al. Histology and Histopathology 20(3):927-937, 2005 and Vollmers et al. Methods and Findings in Experimental and Clinical Pharmacology 27(3): 185-91 , 2005.Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.6. Library- Derived AntibodiesAntibodies disclosed herein may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities (see, e.g., Example 1). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in the McCafferty et al. Nature 348:552-554, 1990; Clackson et al. Nature 352: 624-628, 1991 ; Marks et al. J. Mol. Biol. 222: 581 -597, 1992; Marks et al. in Methods in Molecular Biology 248:161 -175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al. J. Mol. Biol. 338(2): 299-310, 2004; Lee et al. J. Mol. Biol. 340(5): 1073-1093, 2004; Fellouse, Proc. Natl. Acad. Sci. USA 101 (34):12467-12472, 2004; and Lee et al. J. Immunol. Methods 284(1 -2): 1 19-132, 2004.In certain phage display methods, repertoires of variable domains are cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al. Ann. Rev. Immunol., 12: 433-455, 1994. Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al. EMBO J. 12: 725-734, 1993. Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable HVR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom et al. J. Mol. Biol., 227: 381 -388, 1992. Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.7. Multispecific AntibodiesAn antibody provided herein may be a multispecific antibody, for example, a bispecific antibody.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Multispecific antibodies are antibodies that have binding specificities for at least two different sites. In certain instances, bispecific antibodies may bind to two different epitopes of IL23R. One of the binding specificities may be for IL23R and the other may be for any other antigen (e.g., a second biological molecule). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.Techniques for making multispecific antibodies include, but are not limited to, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein et al. Nature 3Q5 537, 1983; WO 93 / 08829; and Traunecker et al. EMBO J. 10: 3655, 1991), and “knobin-hole” engineering (see, e.g., U.S. Patent No. 5,731 ,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009 / 089004A1); cross-linking two or more antibodies or fragments (see, e.g., US Patent No. 4,676,980, and Brennan et al. Science, 229: 81 , 1985); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al. J. Immunol., 148(5): 1547- 1553, 1992); using “diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993); and using single-chain Fv (scFv) dimers (see, e.g. Gruber et al. J. Immunol. 152:5368, 1994); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60, 1991.Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g. US 2006 / 0025576A1).The antibody or fragment herein also includes a “Dual Acting Fab” or “DAF” comprising an antigen binding site that binds to IL23R as well as another, different antigen (see, US 2008 / 0069820, for example).Knobs-into-HolesIn some instances, an antibody provided herein may contain an Fc domain that is engineered to produce multispecific antibodies using the "knob-in-hole" method. The use of knobs-into-holes as a method of producing multispecific antibodies is described, e.g., in U.S. Pat. No. 5,731 ,168, WG2009 / 089004, US2009 / 0182127, US2011 / 0287009, Marvin and Zhu, Acta Pharmacol. Sin. (2005) 26(6):649-658, and Kontermann (2005) Acta Pharmacol. Sin., 26:1 -9. A brief nonlimiting discussion is provided below.A “protuberance” refers to at least one amino acid side chain which projects from the interface of a first polypeptide and is therefore positionable in a compensatory cavity in the adjacent interface (i.e. , the interface of a second polypeptide) so as to stabilize the heteromultimer, and thereby favor heteromultimer formation over homomultimer formation, for example. The protuberance may exist in the original interface or may be introduced synthetically (e.g., by altering nucleic acid encoding the interface). In some instances, a nucleic acid encoding the interface of the first polypeptide is altered to encode the protuberance. To achieve this, the nucleic acid encoding at least one “original” amino acid residue in the interface of the first polypeptide is replaced with nucleic acid encoding at least one “import” amino acid residue which has a larger side chain volume than the original amino acid residue. It will be appreciated that there can be more than one original and corresponding import residue. The side chain volumes of thePATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 various amino residues are shown, for example, in Table 1 of US 2011 / 0287009 or Table 1 of U.S. Patent No. 7,642,228.In some instances, import residues for the formation of a protuberance are naturally occurring amino acid residues selected from arginine (R), phenylalanine (F), tyrosine (Y) and tryptophan (W). An import residue may be tryptophan or tyrosine. In some instances, the original residue for the formation of the protuberance has a small side chain volume, such as alanine, asparagine, aspartic acid, glycine, serine, threonine, or valine. See, for example, U.S. Patent No. 7,642,228.A “cavity” refers to at least one amino acid side chain which is recessed from the interface of a second polypeptide and therefore accommodates a corresponding protuberance on the adjacent interface of a first polypeptide. The cavity may exist in the original interface or may be introduced synthetically (e.g., by altering nucleic acid encoding the interface). In some instances, nucleic acid encoding the interface of the second polypeptide is altered to encode the cavity. To achieve this, the nucleic acid encoding at least one “original” amino acid residue in the interface of the second polypeptide is replaced with DNA encoding at least one “import” amino acid residue which has a smaller side chain volume than the original amino acid residue. It will be appreciated that there can be more than one original and corresponding import residue. In some instances, import residues for the formation of a cavity are naturally occurring amino acid residues selected from alanine (A), serine (S), threonine (T), and valine (V). In some instances, an import residue is serine, alanine, or threonine. In some instances, the original residue for the formation of the cavity has a large side chain volume, such as tyrosine, arginine, phenylalanine, or tryptophan.The protuberance is “positionable” in the cavity which means that the spatial location of the protuberance and cavity on the interface of a first polypeptide and second polypeptide respectively and the sizes of the protuberance and cavity are such that the protuberance can be located in the cavity without significantly perturbing the normal association of the first and second polypeptides at the interface. Since protuberances such as Tyr, Phe, and Trp do not typically extend perpendicularly from the axis of the interface and have preferred conformations, the alignment of a protuberance with a corresponding cavity may, in some instances, rely on modeling the protuberance / cavity pair based upon a three-dimensional structure such as that obtained by X-ray crystallography or nuclear magnetic resonance (NMR). This can be achieved using widely accepted techniques in the art.In certain instances, a knob mutation in an IgG 1 constant region is T366W (EU numbering). A hole mutation in an lgG1 constant region may comprise one or more mutations selected from T366S, L368A, and Y407V (EU numbering). For example, a hole mutation in an lgG1 constant region may comprise T366S, L368A, and Y407V (EU numbering).In certain instances, a knob mutation in an lgG4 constant region is T366W (EU numbering). A hole mutation in an lgG4 constant region may comprise one or more mutations selected from T366S, L368A, and Y407V (EU numbering). For example, a hole mutation in an lgG4 constant region comprises T366S, L368A, and Y407V (EU numbering).PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-18. Antibody VariantsIn certain instances, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody (e.g., protease resistance or evasion of pre-exisiting anti-drug antibodies (e.g., anti-VHH antibodies)). Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen-binding.Substitution, Insertion, and Deletion VariantsIn certain instances, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table 1 under the heading of “preferred substitutions.” More substantial changes are provided in Table 1 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Conservative substitutions can also be found using FIG. 3 (see, e.g., Example 5). Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., protease resistance, retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.Table 1 : Amino Acid SubstitutionsPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Amino acids may be grouped according to common side-chain properties:(1 ) hydrophobic: Norleucine, Met, Ala, Vai, Leu, lie;(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;(3) acidic: Asp, Glu;(4) basic: His, Lys, Arg;(5) residues that influence chain orientation: Gly, Pro;(6) aromatic: Trp, Tyr, Phe.Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Non-conservative substitutions can also be found using FIG. 3 (see, e.g., Example 5).One type of substitutional variant involves substituting one or more HVR (e.g., CDR) residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and / or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, for example, using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g., binding affinity).Alterations (e.g., substitutions) may be made in HVRs (e.g., CDRs), e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196, 2008), and / or residues that contact antigen, with the resulting variant variable domain being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O’Brien et al. ed., Human Press, Totowa, NJ, 2001 ). In some examples of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residuesPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. HVR-H3 and HVR-L3 in particular are often targeted.Substitutions, insertions, or deletions may occur within one or more HVRs (e.g., CDRs) so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may, for example, be outside of antigen contacting residues in the HVRs. In certain instances of the variant variable domain sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham et al. Science 244:1081 -1085, 1989. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., Ala or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue (e.g., one carboxyl-terminal alanine residue) to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.Glycosylation VariantsAn antibody or antibody fragment provided herein may be altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32, 1997. The oligosaccharide may include various carbohydrates, for example, mannose, N-acetyl glucosamine (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the “stem” of the biantennary oligosaccharide structure. In some instances, modifications of the oligosaccharide in an antibody disclosed herein may be made in order to create antibody variants with certain improved properties.In some instances, antibody variants may have a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody mayPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e. , between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. 2003 / 0157108 and 2004 / 0093621 . Examples of publications related to “defucosylated” or “fucose- deficient” antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621 ; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO 2005 / 053742; WO 2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249, 2004; Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614,2004. Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545, 1986; US 2003 / 0157108; and WO 2004 / 056312 A1 , especially at Example 11), and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614, 2004; Kanda et al. Biotechnol. Bioeng. 94(4):680-688, 2006; and WO 2003 / 085107).Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003 / 011878; US Patent No. 6,602,684; and US 2005 / 0123546. Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.Fc Region VariantsOne or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG 1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.An antibody variant that possesses some but not all effector functions is contemplated herein, which makes it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RII I only, whereas monocytes express Fc(RI, Fc(RII and Fc(RI II . FcR expression on hematopoietic cells is summarized in Table 3 on page 464 ofPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Ravetch et al. Annu. Rev. Immunol. 9:457-492, 1991 . Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom et al. Proc. Natl. Acad. Sci. USA 83:7059-7063, 1986 and Hellstrom et al. Proc. Natl. Acad. Sci. USA 82:1499-1502, 1985; U.S. Patent No. 5,821 ,337 (see Bruggemann et al. J. Exp. Med. 166:1351 -1361 , 1987). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ nonradioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA 95:652-656, 1998. C1 q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1 q and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, e.g., Gazzano-Santoro et al. J. Immunol. Methods 202:163, 1996; Cragg et al. Blood 01 :1045-1052, 2003; and Cragg et al. Blood 03:2738-2743, 2004). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, e.g., Petkova et al. Inti. Immunol. 18(12) : 1759-1769, 2006).Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581).Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004 / 056312; and Shields et al. J. Biol. Chem. 9(2): 6591 -6604, 2001).In certain instances, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues).In certain instances, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) C1q binding and / or Complement Dependent Cytotoxicity (CDC), for example, as described in US Patent No. 6,194,551 , WO 99 / 51642, and Idusogie et al. J. Immunol. 164: 4178-4184, 2000.Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al. J. Immunol. 117:587, 1976 and Kim et al. J. Immunol. 24:249, 1994), are described in US2005 / 0014934. Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).See also Duncan et al. Nature 322:738-40, 1988; U.S. Patent Nos. 5,648,260 and 5,624,821 ; and WO 94 / 29351 concerning other examples of Fc region variants.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1Cysteine Engineered Antibody VariantsIn certain instances, it may be desirable to create cysteine engineered antibodies, for example, “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular instances, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linkerdrug moieties, to create an immunoconjugate, as described further herein. For example, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, e.g., in U.S. Patent No. 7,521 ,541 .Antibody DerivativesAn antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3, 6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide / ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.Conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one example, the nonproteinaceous moiety is a carbon nanotube (Kam et al. Proc. Natl. Acad. Sci. USA 102: 11600-1 1605, 2005). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody- nonproteinaceous moiety are killed.Protease-Resistant VariantsAn antibody provided herein may be further modified to reduce sensitivity to proteolysis or resist cleavage by one or more proteases. In some instances, a polypeptide is said to be resistant to proteolysis when, in a population of polypeptides, only a proportion of the polypeptides are cleaved by the protease; control populations include mock-treated polypeptides, for example. Modifications to antibodies provided herein can include addition, deletion, or substitution of amino acid residues. Protease substrates arePATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 cleaved at the peptide bond between the amino acid residues that occupy P1 and P1 amino acid residues that are amino terminal to P1 are number P2, P3, P4, etc., and for those that are to the carboxy side of the substrate of P1 ’ are analogously annotated P2’, P3’, P4’, etc.; thus a cleavage site on substrate that is cleaved into two tetrapeptides, for example, is designated: P4-P3-P2-P1 -P1 ’-P2’-P3’-P4’. In some instances, a modification is at the P4, P3, P2, P1 , P1 ’, P2’, P3', or P4’ position of the protease cleavage site. The modification to the amino acid sequence can render the protease cleavage site non- cleavable or less sensitive to cleavage. Table 2 shows certain cleavage sites of an anti-IL23R VHH antibody clone 2A8, as found in Example 5 in the Examples. The “Site” column indicates the residue at P1 (Kabat numbering).Table 2: Example sites of proteolysis in anti-IL23R VHH antibody clone 2A8 (See Example 5)In certain instances, the protease cleavage site is a chymotrypsin cleavage site which contains a W, Y, F, L, M, or H in the P1 position. In some instances, the chymotrypsin cleavage site is disrupted by deletion of the amino acid residue in the P1 position. In some instances, the chymotrypsin cleavage site is disrupted by substitution of the amino acid in the P1 position with an amino acid residue that is less sensitive to chymotrypsin cleavage (e.g., an amino acid residue that is not W, Y, F, L, M, or H). In some instances, the chymotrypsin cleavage site is disrupted by incorporation of a D or Q in the P1 ' position.In certain instances, the protease cleavage site is a trypsin cleavage site which contains a R or K in the P1 position. In some instances, the trypsin cleavage site is disrupted by deletion of the amino acid residue in the P1 position. In some instances, the trypsin cleavage site is disrupted by substitution of the amino acid in the P1 position with an amino acid residue that is less sensitive to trypsin cleavage (e.g., an amino acid residue that is not R or K). In some instances, the trypsin cleavage site is disrupted by incorporation of a P in the P1 ' position. In some instances, the trypsin cleavage site is disrupted by incorporation of a P in the P2’ position.In certain instances, the protease cleavage site is an elastase cleavage site which contains an A,V, S, G, L, or I in the P1 position. In some instances, the elastase cleavage site is disrupted by deletion of the amino acid residue in the P1 position. In some instances, the elastase cleavage site is disrupted by substitution of the amino acid in the P1 position with an amino acid residue that is less sensitive to elastase cleavage (e.g., an amino acid residue that is not A, V, S, G, L, or I).In certain instances, the protease cleavage site is a pepsin cleavage site which contains an F, Y,W, or L in the P1 or P1 ’ position. In some instances, the pepsin cleavage site is disrupted by deletion of amino acid residue in the P1 position. In some instances, the pepsin cleavage site is disrupted byPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 substitution of the amino acid in the P1 position with an amino acid residue that is less sensitive to pepsin cleavage (e.g., an amino acid residue besides F, Y, W, or L). In some instances, the pepsin cleavage site is disrupted by incorporation of a P in the P2, P1 , P1 P2’, or P3’ positions. In some instances, the pepsin cleavage site is disrupted by incorporation of a R, K, or H in the P3 position.Variants Exhibiting Reduced Binding to Pre-Existing Anti-Drug AntibodiesAn antibody provided herein may be further modified to decrease or eliminate binding by preexisting anti-drug antibodies (e.g., anti-VHH antibodies) in a subject (e.g., a human). Modifications to antibodies provided herein can include addition, deletion, or substitution of amino acid residues. In some instances, modifications can be made to epitopes known to be susceptible to binding by pre-existing antidrug antibodies (e.g., anti-VHH antibodies).In some instances, the pre-existing anti-drug antibodies are anti-VHH antibodies. In particular instances, the amino acid modification results in one or more of (a) a Q at position 110 (Kabat numbering), (b) a Q at position 112 (Kabat numbering), and (c) an A at position 114 (Kabat numbering). In some instances, the modification results in a Q at position 110 (Kabat numbering). In some instances, the modification results in a Q at position 112 (Kabat numbering). In some instances, the modification results in an A at position 114 (Kabat numbering). In some instances, the modification results in a Q at position 110 and a Q at position 112 (Kabat numbering). In some instances, the modification results in a Q at position 110 and an A at position 114 (Kabat numbering). In some instances, the modification results in a Q at position 112 and an A at position 114 (Kabat numbering). In some instances, the modification results in a Q at position 110, a Q at position 112, and an A at position 114 (Kabat numbering). In some instances, the modification includes one or more of (a) a T110Q substitution, (b) a S112Q substitution, and (c) an A1 14 addition (Kabat numbering). In some instances, the modification is a T110Q substitution (Kabat numbering). In some instances, the modification is a S112Q substitution (Kabat numbering). In some instances, the modification is an A114 addition. In some instances, the modification is a T110Q substitution and a S112Q substitution (Kabat numbering). In some instances, the modification is a T110Q substitution and an A114 addition (Kabat numbering). In some instances, the modification is a S112Q substitution and an A114 addition (Kabat numbering). In some instances, the modification is a T110Q substitution, a S112Q substitution, and an A114 addition (Kabat numbering).In certain instances, the subject is a human.A. Recombinant Methods and CompositionsAntibodies may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In some instances, one or more isolated nucleic acids may encode an anti-IL23R VHH antibody fragment described herein. For example, in some instances, one or more nucleic acids may encode an amino acid sequence of a multispecific anti-IL23R VHH antibody comprising a VHH and an amino acid sequence comprising a VL and / or an amino acid sequence comprising a VH of the antibody (e.g., the light and / or heavy chains of the antibody). Also described herein are one or more vectors (e.g., expression vectors) comprising such nucleic acids. In some instances, a host cell may comprise such nucleic acids. For example, in some instances, a host cellPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 comprises (e.g., has been transformed with) a vector comprising one or more nucleic acids that encode an amino acid sequence comprising the anti-IL23R VHH antibody. In another example, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the VHH antibody and an amino acid sequence comprising the VH of the VHH antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the VHH antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the VHH antibody. In some instances, the host cell is eukaryotic, for example, a Chinese Hamster Ovary (CHO) cell, 293 cell, or lymphoid cell (e.g., Y0, NSO, Sp20 cell). In certain examples, the host cell is a mammalian cell (e.g., a CHO cell). In certain examples, the host cell is a prokaryotic cell (e.g., E. coli).A method of making an anti-IL23R VHH antibody is provided herein, wherein the method comprises culturing a host cell comprising one or more nucleic acids encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).For recombinant production of an anti-IL23R VHH antibody, one or more nucleic acids encoding a VHH antibody, for example, as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy or light chains of the antibody).Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli). After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See, e.g., Gerngross Nat. Biotech. 22:1409-1414, 2004 and Li et al. Nat. Biotech. 24:210-215, 2006.Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.Plant cell cultures can also be utilized as hosts. See, for example, US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkeyPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al. J. Gen Virol. 36:59, 1977); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather Biol. Reprod. 23:243-251 , 1980); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68, 1982; MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include CHO cells, including DHFR- CHO cells (Urlaub et al. Proc. Natl. Acad. Sci. USA 77:4216, 1980); and myeloma cell lines such as Y0, NS0 and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki et al. Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268, 2003.B. Assays Anti-IL23R VHH antibodies provided herein may be identified, screened for, or characterized for their physical / chemical properties and / or biological activities by various assays known in the art. a) Binding AssaysAn anti-IL23R VHH antibody disclosed herein can be tested for its antigen-binding activity, for example, by known methods such as ELISA, SPR, Western blot, and the like.Competition assays may be used to identify an antibody that competes with an anti-IL23R VHH antibody disclosed herein for binding to IL23R. In certain instances, the antibody that competes with the anti-IL23R VHH antibody is a VHH antibody. In certain instances, such a competing antibody binds to the same epitope (e.g., a linear or a conformational epitope) that is bound by an anti-IL23R VHH antibody disclosed herein. In some instances, the epitope is within the D1 domain of IL23R. Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris “Epitope Mapping Protocols,” in Methods in Molecular Biology \ / o\. 66 (Humana Press, Totowa, NJ), 1996.In an exemplary competition assay, immobilized IL23R is incubated in a solution comprising a first labeled antibody that binds to IL23R and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to IL23R. The second antibody may be present in a hybridoma supernatant. As a control, immobilized IL23R is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to IL23R, excess unbound antibody is removed, and the amount of label associated with immobilized IL23R is measured. If the amount of label associated with immobilized IL23R is substantially reduced in the test sample relative to the control sample, then that indicates that the second antibody is competing with the first antibody for binding to IL23R. See, e.g., Harlow et al. Antibodies: A Laboratory Manual Ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), 1988. b) Activity AssaysAssays that measure anti-IL23R VHH antibody biological activity can be used to identify such antibodies as well as to quantify their activity. Examples of biological activity that can be measuredPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 include binding to IL23R (e.g., IL23R on immune cells), or a peptide fragment thereof; blocking or neutralizing IL23R, or preventing IL23R from binding to a ligand (e.g., IL23); and binding to the D1 domain of IL23R and blocking of binding to the IL23. Antibodies having such biological activity in vivo, in vitro, and / or ex vivo are also provided. In some instances, an antibody disclosed herein is tested for such biological activity. For example, an anti-IL23R VHH antibody disclosed herein can be tested for inhibition in a cell-based IL23R blocking assay. For example, cell-blocking assays can be used; in these assays, such as those described in Example 7, the antibody is tested for its ability to inhibit IL23R-induced reporter activity in a target cell, which can be a primary cell, such as a PBMC, which can be a human PBMC. The IL23R-induced reporter activity can be the induction of IL17F production in a human PBMC assay. In another example, an antibody disclosed herein is tested for inhibiting the binding of IL23 to IL23R in a competitive binding ELISA. In another example, an antibody disclosed herein is tested for inhibiting the binding of IL23 to IL23R in a surface plasmon resonance (SPR)-based competitive binding assay. In some instances, an antibody that can inhibit an IL23R activity by about 90% or greater (e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) is defined as a complete inhibitor and an antibody that can inhibit an IL23R activity by between about 1% and about 89% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%,56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or 89%) is defined as a partial inhibitor (e.g. when compared to an appropriate control, such as a control antibody or peptide described, for example, in Example 7).C. ImmunoconjugatesThe invention also provides immunoconjugates comprising an anti-IL23R VHH antibody provided herein conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or molecules used for detection, for example, as described in Section E below.In one non-limiting example, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701 , 5,770,710, 5,773,001 , and 5,877,296; Hinman et al. Cancer Res. 53:333623R42, 1993; and Lode et al. Cancer Res. 58:2925-2928, 1998); an anthracycline such daunomycin or doxorubicin (see Kratz et al. Current Med. Chem. 13:477-523, 2006; Jeffrey et al. Bioorganic & Med. Chem. Letters 16:358-362, 2006; Torgov et al. Bioconj. Chem. 16:717- 721 , 2005; Nagy et al. Proc. Natl. Acad. Sci. USA 97:829-834, 2000; Dubowchik et al. Bioorg. & Med. Chem. Letters 12:1529-1532, 2002; King et al. J. Med. Chem. 45:4336-4343, 2002; and U.S. Patent No.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-16,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.In another example, an immunoconjugate comprises an antibody as described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.In another example, an immunoconjugate comprises an antibody as described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example technetium-99m (tc99m) or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine- 123 again, iodine-131 , indium-1 1 1 , fluorine- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al. Science 238:1098, 1987. Carbon-14-labeled 1 -isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See, e.g., WO 94 / 1 1026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (see, e.g., Chari et al. Cancer Res. 52:127-131 , 1992; U.S. Patent No. 5,208,020) may be used.The immunoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).D. Methods and Compositions for Diagnostics and DetectionAny of the anti-IL23R VHH antibodies provided herein may be used for detecting the presence of IL23R in a sample (e.g., a biological sample). The term “detecting” as used herein encompassesPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 quantitative or qualitative detection. For example, a biological sample may comprise a cell or tissue, such as blood, blood cells (e.g., macrophages, innate type II (ILC2) cells, mast cells, basophils, eosinophils, and dendritic cells), smooth muscle, epithelial cells, endothelial cells, or central nervous system cells (e.g., glia cells).An anti-IL23R VHH antibody suitable for use in a method of diagnosis or detection is described herein, such as a method of detecting the presence or level of IL23R in a biological sample. In certain instances, the method comprises contacting the biological sample with an anti-IL23R VHH antibody as described herein under conditions permissive for binding of the anti-IL23R VHH antibody to IL23R, and detecting whether a complex is formed between the anti-IL23R VHH antibody and IL23R. Such method may be an in vitro or in vivo method. In some instances, the anti-IL23R VHH antibody is conjugated to a molecule used for detection (e.g., radioactive isotopes (e.g., zirconium 89), fluorophores, enzymes (e.g., horseradish peroxidase or luciferase)). In some instances, an anti-IL23R VHH antibody is used to select subjects eligible for therapy with an anti-IL23R VHH antibody, for example, where IL23R is a biomarker for selection of patients.Exemplary disorders that may be diagnosed using an antibody disclosed herein include IL23- mediated diseases and disorders (e.g., gastrointestinal-related (Gl-related) disease (e.g., an inflammatory bowel disease (IBD) , a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation)).In some instances, the IL23-mediated disease or disorder is a Gl-related disease. In some instances, the Gl-related disease is an IBD. In some instances, the IBD is ulcerative colitis (UC) or Crohn’s disease (CD).Tagged or labeled anti-IL23R VHH antibodies are also described herein. Tags or labels include, but are not limited to, labels or moieties that are detected directly (such as fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels), as well as moieties, such as enzymes or ligands, that are detected indirectly, e.g., through an enzymatic reaction or molecular interaction. Exemplary labels include, but are not limited to, the radioisotopes32P,14C,125l,3H, and131l, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luceriferases, e.g., firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, p- galactosidase, glucoamylase, lysozyme, saccharide oxidases, e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase, coupled with an enzyme that employs hydrogen peroxide to oxidize a dye precursor such as HRP, lactoperoxidase, or microperoxidase, biotin / avidin, spin labels, bacteriophage labels, stable free radicals, and the like.E. Pharmaceutical FormulationsPharmaceutical formulations (pharmaceutical compositions) of an anti-IL23R VHH antibody disclosed herein can be prepared by mixing such antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers, excipients, or diluents (see, e.g., Remington'sPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980), in the form of lyophilized formulations or aqueous solutions.A pharmaceutical composition of the disclosed anti-IL23R VHH antibodies can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration varies depending upon the desired results. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. Supplementary active compounds can also be incorporated into the compositions.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and WO 2006 / 044908, the latter formulations including a histidine-acetate buffer.The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980.Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.The present invention relates generally to anti-IL23R VHH antibodies that have IL23R antagonist activity. In certain instances, this invention provides for the oral delivery of antagonists of IL23. IL23- mediated diseases and disorders (e.g., Gl-related diseases) have characteristics that can include local inflammation of the intestinal tissue; therefore, advantageous therapeutic agents would act from the luminal side of the intestine, yielding high drug concentrations in diseased tissue, minimizing systemic availability and resulting in improved efficacy and safety when compared to systemic approaches. Thus, in some instances, oral administration of the anti-IL23R VHH antibodies of the present invention is expected to maximize drug levels in diseased Gl tissues while limiting drug concentrations in circulation, thereby providing efficacious, safe, and durable delivery for treatment of Gl-related diseases and disorders.In certain instances, the anti-IL23R VHH antibody is formulated for oral delivery, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into drink or food. For oral therapeutic administration, the anti-IL23R VHH antibodies of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. Oral formulations including antibodies are described in Jaison et al., Nutrition Journal. 14:22 (2015), which is incorporated herein by reference in its entirety. For example, the anti-IL23R VHH antibodies may be formulated in a lyophilized composition, mixed into a liquid or a powder formulation. In some embodiments, the anti-IL23R VHH antibodies are formulated in capsules including the antibodies. The anti-IL23R VHH antibodies may be formulated in enteric-coated capsules containing the antibodies. In some embodiments, the anti-IL23R VHH antibodies are formulated in capsules that are not enteric coated. The enteric-coated capsules may be filled with mini-tablets of spray-dried anti-IL23R VHH antibody. The mini-tables can include, for example, 150 mg of the VHH antibody. The mini-tables can include, for example, 300 mg of the VHH antibody. In some embodiments, the mini-tablets includePATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 mannitol. For example, the minitablets can comprise mannitol at a ratio of 5 mg of the VHH antibody to 1 mg of mannitol. In some embodiments, the minitablets include histidine. In some embodiments, the minitablets include histidine hydrochloride. In some embodiments, the mini-tablets are seal coated, e.g., with OPADRY® II White using a O’Hara LABCOAT™ M. In some embodiments, the mini-tablets are enteric coated. In some embodiments, the mini-tablets are suspended in a medium, e.g., a medium with a pH of about 3.5, e.g., a medium with a pH of 3.5. An antibody disclosed herein may be combined, for example, with orally acceptable preservatives, co-solvents, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and / or water. Preservatives may be included, for example, to inhibit microbial contamination during use. Suitable preservatives include: edetate disodium, methyl paraben, propyl paraben, sorbic acid, phenylethyl alcohol, chlorobutanol, polyquaternium-1 , or other agents known in the art. Such preservatives are typically employed at a level of from 0.001 to 1 .0% w / v. In some instances, a pharmaceutical formulation disclosed herein does not include a preservative. In certain instances, compositions intended to be administered topically to the rectum. In some instances, the total amount of antibody will be about 0.001 to 1 .0% (w / w), for example, about 0.01 to about 1 .0% (w / w), of such a formulation. The composition formulated for oral administration may contain at least 0.01% (w / v) of the antibody. For example, the composition may contain about 0.1% to 70% (w / v) of the antibody, e.g., about 0.1% to 65% (w / v), about 0.1% to 65% (w / v), about 0.1% to 55% (w / v), about 0.1% to 50% (w / v), about 0.1% to 45% (w / v), about 0.1% to 40% (w / v), about 0.1% to 35%(w / v), about 0.1% to 30% (w / v), about 0.1% to 25% (w / v), about 0.1% to 20% (w / v), about 0.1% to 15% (w / v), about 0.1% to 10% (w / v), about 0.1% to 5% (w / v), about 0.1% to 2% (w / v), about 2% to 70% (w / v), or about 2% to 60% (w / v) of the antibody.The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, for example, by filtration through sterile filtration membranes. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants, such as TWEEN® 80. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be broughtPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.An anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) can be formulated in a polymeric formulation.Any suitable concentration of any of the antibodies disclosed herein may be used in the compositions (e.g., pharmaceutical compositions). For example, the concentration of an antibody in a composition disclosed herein may range, for example, from about 1 mg / mL to about 400 mg / mL (e.g., about 1 mg / mL to about 400 mg / mL, about 1 mg / mL to about 375 mg / mL, about 1 mg / mL to about 350 mg / mL, about 1 mg / mL to about 325 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 275 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 225 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 175 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 125 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 75 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 25 mg / mL, about 25 mg / mL to about 350 mg / mL, about 25 mg / mL to about 325 mg / mL, about 25 mg / mL to about 300 mg / mL, about 25 mg / mL to about 275 mg / mL, about 25 mg / mL to about 250 mg / mL, about 25 mg / mL to about 225 mg / mL, about 25 mg / mL to about 200 mg / mL, about 25 mg / mL to about 175 mg / mL, about 25 mg / mL to about 150 mg / mL, about 25 mg / mL to about 125 mg / mL, about 25 mg / mL to about 100 mg / mL, about 25 mg / mL to about 75 mg / mL, about 25 mg / mL to about 50 mg / mL, about 50 mg / mL to about 350 mg / mL, about 50 mg / mL to about 325 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 275 mg / mL, about 50 mg / mL to about 250 mg / mL, about 50 mg / mL to about 225 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 175 mg / mL, about 50 mg / mL to about 150 mg / mL, about 50 mg / mL to about 125 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 75 mg / mL, about 75 mg / mL to about 350 mg / mL, about 75 mg / mL to about 325 mg / mL, about 75 mg / mL to about 300 mg / mL, about 75 mg / mL to about 275 mg / mL, about 75 mg / mL to about 250 mg / mL, about 75 mg / mL to about 225 mg / mL, about 75 mg / mL to about 200 mg / mL, about 75 mg / mL to about 175 mg / mL, about 75 mg / mL to about 150 mg / mL, about 75 mg / mL to about 125 mg / mL, about 75 mg / mL to about 100 mg / mL, about 100 mg / mL to about 350 mg / mL, about 100 mg / mL to about 325 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 275 mg / mL, about 100 mg / mL to about 250 mg / mL, about 100 mg / mL to about 225 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 175 mg / mL, about 100 mg / mL to about 150 mg / mL, about 100 mg / mL to about 125 mg / mL, or about 150 mg / mL to about 175 mg / mL).Any suitable amount of any of the antibodies disclosed herein may be used in the compositions (e.g., pharmaceutical compositions). For example, the amount of an antibody in a composition disclosed herein may range, for example, from about 100 pg to about 40 g (e.g., about 200 pg to about 10 g, about 500 pg to about 1000 mg, about 1 mg to about 1000 mg, about 10 mg to about 1000 mg, or about 50 mg to about 500 mg).PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1F. Therapeutic Methods and CompositionsAny of the anti-IL23R VHH antibodies disclosed herein may be used in therapeutic methods. In some instances, an anti-IL23R VHH antibody may be used as a monotherapy. In other instances , an anti-IL23R VHH antibody may be used as in a combination therapy.The invention provides IL23R antibodies for use as medicaments. In one aspect, provided herein is an anti-IL23R VHH antibody for use as a medicament. In further aspects, provided herein is an anti- IL23R VHH antibody for use in treating IL23-mediated diseases and disorders (e.g., Gl-related disease). Also provided herein is an anti-IL23R VHH antibody for use in a method of treatment. In certain instances, an anti-IL23R VHH antibody for use in a method of treating an individual having a Gl-related disease comprises administering to the individual an effective amount of the anti-IL23R VHH antibody. In one such instance, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. An “individual” according to any of the above instances is preferably a human.Provided herein are IL23R antibodies for the manufacture or preparation of a medicament. In a further aspect, provided herein is the use of an anti-IL23R VHH antibody in the manufacture or preparation of a medicament. In one instance, the medicament is for treatment of an IL23-mediated disease or disorder. In another instance, the medicament is for treatment of a Gl-related disease. In a further instance, the medicament is for use in a method of treating an IL23-mediated disease or disorder, e.g., a Gl-related disease comprising administering to an individual having a Gl-related disease an effective amount of the medicament. In one such instance, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below. An “individual” according to any of the above instances may be a human.Also provided herein is a method for treating Gl-related diseases. In some instances, the method comprises administering the individual having a Gl-related disease an effective amount of an IL23R antibody. In one instance, the method comprises administering to an individual having such Gl-related disease an effective amount of an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein). In one such instance, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. An “individual” according to any of the above instances may be a human.Also provided herein is a method for treating an individual at risk of developing an IL23-mediated disease or disorder, such as but not limited to a Gl-related disease. In one instance, the method comprises administering to an individual at risk of developing an IL23-mediated disease or disorder, e.g., a Gl-related disease, an effective amount of an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein). In one instance, the method comprises administering to an individual at risk of developing an IL23-mediated disease or disorder, e.g., a Gl-related disease, an effective amount of an anti-IL23R VHH antibody having a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1 ), wherein Xi is A or S; (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2is G or D; and (c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V. In one instance, the method comprises administeringPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 to an individual at risk of developing an IL23-mediated disease or disorder, e.g., a Gl-related disease, an effective amount of an anti-IL23R VHH antibody having a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1G (SEQ ID NO: 5), wherein Xi is V or T; and (c) a CDR-H3 comprising the amino acid sequence of KRPX1AGWX2TYDY (SEQ ID NO: 6), wherein Xi is D or G, and X2 is Q, S, or D. In one instance, the method comprises administering to an individual at risk of developing an IL23-mediated disease or disorder, e.g., a Gl-related disease, an effective amount of an anti-IL23R VHH antibody having a binding domain including (a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4); (b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and (c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8). In one such instance, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. An “individual” according to any of the above instances may be a human.In a further aspect, the invention provides pharmaceutical formulations comprising any of the anti- IL23R VHH antibodies provided herein, e.g., for use in any of the above therapeutic methods. In one instance, a pharmaceutical formulation comprises any of the anti-IL23R VHH antibodies provided herein and a pharmaceutically acceptable carrier. In some instances, a pharmaceutical formulation comprising any of the anti-IL23R VHH antibodies provided herein is suitable for oral administration. Oral formulations including antibodies are described in Jaison et al., Nutrition Journal. 14:22 (2015), which is incorporated herein by reference in its entirety. In another instance, a pharmaceutical formulation comprises any of the anti-IL23R VHH antibodies provided herein and at least one additional therapeutic agent, for example, as described below.In any of the preceding aspects, the Gl-related disease may be a Gl-related disease, e.g., an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation.In some instances, the IBD may be UC or CD. In some instances, the gut-associated infection may be a Salmonella infection or a Clostridium difficile infection.An anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) can be used either alone or in combination with other agents in a therapy (e.g., an anti-cancer therapy or an anti- integrin antibody (e.g., vedolizumab or etrolizumab)). For instance, an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) may be co-administered with at least one additional therapeutic agent. In some instances, an additional therapeutic agent is a chemotherapeutic agent, an anti-integrin antibody (e.g., vedolizumab or etrolizumab), an anti-hormonal agent, a cytotoxic agent, a growth inhibitory agent, or combinations thereof. In some instances, the additional therapeutic agent is vedolizumab. In some instances, the additional therapeutic agent is etrolizumab.An anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) for use in any of the methods described herein can be formulated in a polymeric formulation.For example, in certain instances, any of the preceding methods further comprises administering one or more additional compounds. In certain instances, the anti-IL23R VHH antibody or polymeric formulation is administered simultaneously with the additional compound(s). In certain instances, the anti-PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1IL23R VHH antibody or polymeric formulation is administered before or after the additional compound(s). In certain instances, the additional compound is an antibody or antigen-binding fragment thereof. In certain instances according to (or as applied to) any of the instances above, the Gl-related disease is selected from the group consisting of an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, and pathogenic inflammation. For example, in some instances, the additional compound is a bispecific antibody.In some instances, an antibody of the invention, and / or polymeric formulation thereof, can be administered in combination with at least one additional therapeutic agent for treatment of a Gl-related disease, for example, a Gl-related disease described herein (e.g., an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, and pathogenic inflammation).An antibody of the invention, and / or polymeric formulation thereof, may be administered in combination with a therapy or surgical procedure for treatment of a IL23-mediated disease or disorder described herein (e.g., Gl-related disease described herein (e.g., an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, and pathogenic inflammation)), including, for example surgery, use of RNA interference (RNAi), stem cell therapy, gene replacement therapy, and combinations thereof. Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the antibody of the invention can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent or agents. Administration of the anti-IL23R VHH antibody or polymeric formulation and administration of an additional therapeutic agent can occur within about one, two, three, four, or five months, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other.Any of the anti-IL23R VHH antibodies described herein may be administered in combination with an IL23R binding antagonist.Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the antibody disclosed herein can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent or agents. Administration of the anti-IL23R VHH antibody and administration of an additional therapeutic agent can occur within about one month, or within about one, two or three weeks, or within about one, two, three, four, five, or six days, of each other. Antibodies disclosed herein can also be used in combination with radiation therapy.An anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) (and any additional therapeutic agent) can be administered by any suitable means, including orally, intrarectally, mucosally, intravenously, parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some instances, an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein) may be administered orally, intrarectally, mucosally,PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 intravenously, intramuscularly, intradermally, transdermally, subcutaneously, percutaneously, intraarterially, intraperitoneally, intravitreally, topically, intralesionally, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intratumorally, intraperitoneally, peritoneally, intraventricularly, intracranially, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, intraorbitally, ocularly, intraocularly, juxtascleral ly, subtenonly, superchoroidally, by inhalation, by injection, by eye drop, by implantation, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. Preferably, the anti-IL23R VHH antibodies disclosed herein are administered orally. The compositions utilized in the methods described herein can also be administered systemically or locally. Dosing can be by any suitable route, for example, by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. The individual can be pretreated to adjust the pH of the Gl tract (e.g., increase the pH of the stomach or lower the pH of the intestine). Various dosing schedules including but not limited to single or multiple administrations over various timepoints, bolus administration, and pulse infusion are contemplated herein.Antibodies disclosed herein would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The antibody need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically / cli nically determined to be appropriate.For the prevention or treatment of an IL23-mediated disease, e.g., a Gl-related disease, the appropriate dosage of an antibody disclosed herein (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 pg / kg to 100 mg / kg (e.g., 0.01 mg / kg to about 45 mg / kg, e.g., about 0.01 mg / kg to about 40 mg / kg, e.g., about 0.01 mg / kg to about 35 mg / kg, e.g., about 0.01 mg / kg to about 30 mg / kg, e.g., about 0.01 mg / kg to about 25 mg / kg, e.g., about 0.01 mg / kg to about 20 mg / kg, e.g., about 0.01 mg / kg to about 15 mg / kg, e.g., about 0.01 mg / kg to about 10 mg / kg, e.g., about 0.1 mg / kg to about 10 mg / kg, e.g., or about 1 mg / kg to about 10 mg / kg) of antibody can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. In one example, the antibody used is about 10 mg / kg, preferably administered orally. One typical daily dosage might range from about 1 pg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeatedPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the antibody would be in the range from about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, e.g. every week, every two weeks, every three weeks, or every four weeks (e.g., such that the patient receives from about two to about twenty, or e.g., about six doses of the antibody). For example, a dose may be administered once per month (e.g., by subcutaneous injection) as an initial higher loading dose, followed by one or more lower doses may be administered. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response and duration for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level depends upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose is that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends upon the factors described above. If desired, the effective daily dose of therapeutic compositions may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. While possible to administer the anti-IL23R antibodies alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).The anti-IL23R VHH antibodies of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery. Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P.G. Bloeman et al. (1995) FEBS Lett. 357:140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134), different species of which may comprise the formulations of the inventions, as well as components of the invented molecules; p 120 (Schreier et al.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1(1994) J. Biol. Chem. 269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods 4:273. The therapeutic compounds of the invention can be formulated in liposomes, such as liposomes that include a targeting moiety. The therapeutic compounds in the liposomes may be delivered by bolus injection. The composition must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.Alternatively, genes encoding the anti-IL23R VHH antibodies of the invention may be delivered directly into the subject for expression rather than administering purified antibodies for prevention or therapy. For example, viral vectors, such as recombinant viruses, can be used to deliver a nucleic acid encoding anti-IL23R VHH antibodies of the invention. In one example, rAAV virus particles can be used to deliver a nucleic acid encoding anti-IL23R VHH antibodies of the invention (Balazs et al. Nature. 481 : 81 , 2012). Nucleic acid could also be effectively delivered by electroporation of muscle cells with plasmid DNA encoding anti-IL23R VHH antibodies of the invention (Muthumani et al. Hum Vaccin Immunother. 10: 2253, 2013). Lentivirus vectors capable of delivering transgenes could also be used to deliver a nucleic acid encoding anti-IL23R VHH antibodies of the invention.It is understood that any of the above formulations or therapeutic methods may be carried out using an immunoconjugate disclosed herein instead of, or in addition to, an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein).G. Articles of ManufactureAn article of manufacture containing materials useful for the treatment, prevention and / or diagnosis of the diseases or disorders described above is provided herein. The article of manufacture may include an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein). The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers can be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and / or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody disclosed herein. The label or package insert indicates that the composition is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody disclosed herein; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. The article of manufacture in this embodiment disclosed herein may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, dextrose solution, and sodium bicarbonate solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Any of the above articles of manufacture may include an immunoconjugate disclosed herein in place of or in addition to an anti-IL23R VHH antibody (e.g., any anti-IL23R VHH antibody disclosed herein).IV. EXAMPLESThe following are examples of methods and compositions of the disclosed anti-IL23R antibodies. It is understood that various other embodiments can be practiced, given the general description provided above.Table of ExamplesExample 1 : Materials and Methods for the Development and Characterization of Anti-IL23R VHH AntibodiesThis example provides materials and methods for Examples 2-7, which characterize the blocking anti-IL23R VHH antibodies described herein.Anti-IL23R Antibody GenerationLlamas were immunized with either of two antigens, a C-terminal Fc-tagged human IL23 receptor (IL23R-Fc) or a C-terminal histidine-tagged human IL23R (IL23R-His) using standard immunization protocols (Ghahroudi et al. FEBS 1997). Using standard RT-PCR methods, the VHH heavy chain repertoire was amplified and cloned into a phagemid vector to construct an immune phage library. Several rounds of in vitro selections with the phage libraries were then performed using either the IL23R- His or IL23R-Fc with varying concentrations, wash times, and elution conditions. After three and fourPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 rounds of selections, individual phage clones were characterized by enzyme-linked immunosorbent assay (ELISA) and subjected to Sanger sequencing.Expression and Purification of Anti-IL23R VHH AntibodiesUnique sequences identified from phage panning were expressed in a mammalian expression vector containing a C-terminal His tag. The expressed VHHs were subjected to two-step purification: Ni Sepharose excel histidine-tagged protein purification resin (GE Healthcare) followed by size-exclusion chromatography (SEC). VHH antibodies without tags were also expressed in mammalian cells. Untagged VHHs were subjected to ion exchange purification (SP column) or a recombinant protein A resin (GORE) followed by SEC.Surface Plasmon Resonance MethodsSPR experiments were carried out on the BIACGRE®T200 (GE Healthcare) at 37°C using HBS- P+ (GE Healthcare) running buffer. 1 .5 pg / mL of IL23R-FC was captured using an anti-HulgG1 Fc capture kit (GE Healthcare) and monomeric VHHs were added as the analyte in solution at a flow rate of 30uL / min. The VHH was titrated using a dilution series from 100 - 0 nM. Sensorgrams were fit to a 1 :1 Langmuir model to identify kinetic parameters.In vitro Protease Cleavage AssayVHHs were incubated with either single enzymes (trypsin, chymotrypsin, or elastase), pancreatin (a mixture of amylase, lipase, and protease isolated from the pancreas; Sigma Aldrich), or pooled mouse small intestinal (SI) fluid. Sequencing grade trypsin (Sigma catalog # 11418025001), sequencing grade chymotrypsin (Sigma catalog # 11418467001), and elastase (Worthington Biochemical catalog # LS006365) were used at the following concentrations: 500 pg / mL, 100 pg / mL, and 1000 pg / mL, respectively. Single enzyme experiments were done with 10 pg of VHH incubated in PBS with enzyme at 37°C for 1 -4 hours. Reactions were quenched with sample buffer containing SDS, heated and run on a reducing SDS-page gel. Pancreatin and mouse SI fluid experiments were done with 10-15 pg of VHH in the presence of up to 10 mg / mL of pancreatin or neat mouse SI fluid diluted in FaSSIFv2 solution (Biorelevant). The reactions were incubated at 37°C from 1 -24 hours. The reactions were quenched and analyzed by SDS-PAGE.For the mouse fecal stability, healthy mice were orally treated with 100 pL of gastroprotection solution. Fifteen minutes later, the mice orally received 200 pL of 10 mg / mL VHH 2A8v134 in gastroprotection solution. Mouse fecal samples were collected at 4 hours, pooled, and homogenized in 500uL PBS. Samples were then split and incubated at 37°C for 0, 4, 8, and 24 hrs. Intact VHH was then quantified by ELISA. For the human fecal stability, two healthy adult subjects were recruited to donate stool through the Samples for Science program at Genentech in accordance with Institutional Review Board-approved protocols. Healthy volunteers who had not taken antibiotics within 2 weeks of donation self-collected stool aerobically using commode collection cups. Stool samples were aliquoted on ice by Genentech Biosample and Repository Management, and immediately frozen and stored at -80°C until use. To create the soluble fecal matrix, frozen stool was aliquoted into gentleMACS M tubes (MiltenyiPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Biotec), weighed, and sterile PBS added to a final concentration of 0.1 g / mL. Stool was homogenized for 1 min using a gentleMACS Dissociator (Miltenyi Biotec). Homogenized stool was centrifuged at 4,000 x g for 10 min at 4 °C. The supernatant was transferred into 1 mL aliquots in Eppendorf tubes and frozen at - 80 °C until use. Prior to use, the fecal slurry was centrifuged at 13,000 x g for 2 min at room temperature to remove any insoluble material.Purified IL23R VHH protein was added directly to processed fecal slurry at a final concentration of 200 pg / mL. Protein and fecal slurry were incubated at 37°C. At desired timepoints, the reaction was stopped by adding equal volumes of PBS supplemented with 4x complete Protease Inhibitor Cocktail (Roche), 4 mM phenylmethylsulfonyl fluoride (PMSF), and freezing at -20°C prior to processing the ELISA.Saturation Mutagenesis Analysis of Entire VHH Domain of Anti- 1 L23R VHH AntibodiesA full domain saturation mutagenesis library was synthesized in which each mutant contains a single mutation and the entire library includes all 20 amino acids at every position in the VHH. The synthesized library was cloned into a phagemid vector and subjected to several rounds of phage panning against IL23R-His with decreasing concentrations and increasing wash times. The VHH domains were amplified from the initial library and from the round 3-selected library and subjected to next-generation sequencing (NGS). NGS was done on amplified DNA amplicons using a MiSeq (Illumina) instrument. Enrichment ratios were determined by dividing the frequency of each mutation after 3 rounds of selection by the frequency of each mutation in the initial library.Anti-Drug Antibody AssayVHH variants were coated on Maxisorp plates at 2 pg / mL in PBS overnight at 4°C. Plates were washed with PBS + 0.5% BSA + 0.1% TWEEN® 20 (PBSBT) and blocked for 2 hours at 25°C with 2% BSA. Individual serum samples for 95 different donors were diluted at 1 :50 and incubated with VHH- coated and empty wells for 1 -2 hours at 25°C with shaking. After washing, an anti-human Fc-specific HRP secondary antibody (1 :10,000) was added for 30 min at 25°C with shaking. After washing with PBSBT, plates were developed with TMB substrate for 10 minutes and detected at 650 nm.IL23:IL23R Blocking ELISAA MAXISORP™ 384-well plate was coated with 0.5 pg / mL anti-human IgG Fab'2 (Jackson Laboratory, 109-006-098) in PBS at 4 °C overnight. The assay plate was then blocked with blocking buffer (1x PBS + 0.5% BSA + 15 ppm PROCLIN™) and incubated at room temperature for 1 -2 hours with gentle agitation. After blocking, the plate was washed 6 times with washing buffer (1x PBS + 0.05% TWEEN® 20, pH 7.2) and then incubated with 25 pL of recombinant IL23R-Fc (R&D Systems, 1400-IR) diluted assay diluent buffer (1x PBS + 0.5% BSA + 0.05% TWEEN® 20 + 10 ppm PROCLIN™) at a final concentration of 100 ng / mL. The plate was incubated for 1 hour with gentle agitation followed by washing the plate 6 times with washing buffer.To examine the ability of anti-IL23R biologies to block the IL23R / IL23 interaction, 25 pL of anti- IL23R biologic serially diluted with assay buffer was added to the plate, and the plate was then incubatedPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 at room temperature for 2 hours with gentle agitation. After incubation, the plate was washed 6 times with washing buffer. (In some instances, this washing step was skipped to allow weaker IL23R biologic binders to retain their blocking activity. The method that skips this washing step is specifically to referred as the 'No Wash' protocol). To establish the IL23R / IL23 interaction, 25 pL of recombinant human IL23 (R&D Systems, 1290-IL / CF) was added to the wells at a final concentration of 4 ng / mL in assay buffer. The plate was then incubated at room temperature for 1 hour with gentle agitation.To detect IL23 / IL23R binding, the plate was washed 6 times with washing buffer and then incubated with 25 pL of biotinylated anti-IL12 p40 antibody (BIOLEGEND®, 508802) (at a final concentration 62.5 ng / mL in assay buffer) for 1 hour at room temperature with gentle agitation. The plate was then washed and incubated with HRP-conjugated streptavidin (Amersham GE, RPN4401) (1 :40,000 dilution in assay buffer) for 30 minutes at room temperature with gentle agitation. After the final wash (i.e., sixth time with washing buffer), the plate was developed by adding 25 pL tetramethylbenzidine (TMB) (Moss, TMBE-1000) and incubated for 15 minutes at room temperature. The colorimetric reaction was terminated by the addition of 1 M phosphoric acid. Well optical density (OD) was obtained with an absorbance-based microplate reader at 450 nM.The maximal OD (Max OD) was defined using wells with no anti-IL23R blocking reagent. The minimal OD (Min OD) was defined using wells with no IL23 addition. The percentage of inhibition was defined as: 100 x [1 - (OD of test molecule - Min OD) / (Max OD - Min OD)]. The IC50 was determined by fitting the concentration versus percent of inhibition curve using the four-parameter logistic curve fit method using GraphPad Prism 9 software.Human Primary T cell-based IL23R Blockade AssayHuman peripheral blood mononuclear cells (PBMCs) were isolated from blood obtained from adult healthy donors. PBMCs were cultured in T-cell media containing DMEM high glucose (ThermoFisher), 10% heat inactivated FBS (HyClone, SH30071.03), 1x GlutaMax (Gibco, A12860), 1x Non-Essential Amino Acids (Gibco, 1 1140050) , 1x sodium pyruvate (Gibco, 11360070) and 5 pM 2- mercaptoethanol (Gibco, 31350010).To test the potency and efficacy of IL23R blocking biologies, serially diluted anti-IL23R biologies were added to cell culture containing 2x105PBMCs per well in 96-well flat bottom tissue culture plates (Costar, 3595). Thirty minutes after the addition of the testing molecules, the culture media was treated with 5 pg / mL anti-human CD3 monoclonal antibody (BD Biosciences, 555329), 20 ng / mL human IL1 p (R&D Systems, 201 -LB), 4 ng / mL human IL2 (Peprotech, 200-02), and 40 ng / mL human IL23 (R&D Systems, 1290-IL / CF) to induce the IL23 mediated IL17F cytokine secretion. The final assay volume was 200 pL. The treated PBMCs were then incubated at 37°C in a 5% CO2 incubator for 3 days. After incubation, 150 pL of cell culture supernatant was harvested and stored at -80°C for IL17F quantification.To quantify IL17F secretion, the human IL17F DuoSet ELISA kit (R&D Systems, DY1335B) was used following the manufacturer's protocol. The IL17F concentration from PBMCs cultured without IL23R blockade was used to define the effect of no receptor inhibition. The IL17F concentration from PBMCs without IL23 treatment was used to define 100 percent receptor inhibition. The IC50 was determined byPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 fitting the concentration versus percent of inhibition curve using the four-parameter logistic curve fit method in GraphPad Prism 9 software.Example 2: Characterization of Anti-IL23R VHH Antibodies that Inhibit the IL23-IL23R InteractionThis example describes the identification, blocking activity, and binding activity of the anti-IL23R VHH antibodies disclosed herein.Llamas were immunized with both the IL23R-FC and IL23R-His antigen as described in Example 1 . Immune phage display libraries were then generated and selected in vitro for binding to IL23R. After three or four rounds of selection, clones were sequenced and clustered based on CDR-H3 identity. In total, 61 VHH families were obtained, wherein each family contains all VHHs with CDR-H3 sequences that differ by only 3 amino acids or less. Recombinant monomeric VHHs were expressed, purified, and screened for the ability to inhibit the IL23-IL23R interaction in a cell-based human PBMC functional assay. Human PBMCs were incubated in the presence or absence of recombinant VHHs, and IL17F secretion from the PBMCs was measured. Additionally, the binding affinities of each VHH to both human (hulL23R-Fc) and cynomolgus IL23R (cynolL23R-Fc) were determined by SPR. Screening the VHHs using the cell-based assay showed that there were only seven inhibitory VHHs (1 A10, 1 D4, 1 D1 1 , 1 H3, 2A8, 2D7, and 2F1 ) (FIG. 1 A and Table 3). The binding affinities for the three best inhibitors of human IL23R were 2A8, 1 D1 1 , and 2F1 with KD values of 3 nM, 3 nM, and 28 nM, respectively. These three VHHs were confirmed to block the interaction of IL23-IL23R in a biochemical ELISA without the washing step (FIG. 1 B). The EC50s for 1 D1 1 , 2A8, and 2F1 were 1 .07 nM, 1 .04 nM, and 27.4 nM, respectively. The binding affinities for 2A8, 1 D1 1 , and 2F1 to cyno IL23R were similar with KD of 2 nM, 1 nM, and 14 nM, respectively.Table 3: Inhibitory activity of top anti-IL23R VHHsIn the following examples, the key challenges of VHH discovery and engineering were to balance the following objectives: (1 ) to improve VHH affinity for IL23R without lowering stability; and (2) to improve VHH protease stability by identifying susceptible sites to protease digestion and increasing protease stability without altering affinity.We established physiological assays including the trypsin / chymotrypsin / elastase assay, pancreatin assay, mouse small intestine (SI) assays, and mouse / human feces assay to investigate stability.PATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1Example 3: Pancreatin Stability of Inhibitory Anti-IL23R VHH AntibodiesIn this example, the anti-IL23R VHH antibodies described in Example 2 were evaluated for their stability in the presence of pancreatin, a pancreas secretion containing several proteases.All seven inhibitory VHHs were further evaluated in the pancreatin protease digestion assay to assess stability in a mimetic of small intestine fluid. After one hour in pancreatin, only 2A8 and 2F1 had intact VHH remaining, whereas all other VHHs had been completely degraded (FIG. 2). 2A8 had ~5% of intact VHH remaining after an hour, whereas 2F1 had ~1% of intact VHH remaining after one hour. Both 2A8 and 2F1 were completely degraded by four hours. 1 D11 showed very little protease stability, showing < 25% of intact VHH after only 15 minutes in pancreatin. Based on the inhibitory activity, cross-reactivity to cyno IL23R, and affinity values, 2A8 was identified as the most promising VHH for additional engineering.Example 4: Protease Cleavage Sites in Anti-IL23R VHH Antibody Clone 2A8In this example, in order to improve the stability of 2A8, sites of proteolysis in 2A8 were mapped. The VHH were incubated with individual proteases (trypsin, chymotrypsin, or elastase) as well as pancreatin for various times. The resulting samples were analyzed by 3 methods: SDS-PAGE, Edman sequencing, and intact mass spectrometry. 2A8 was not sensitive to proteolysis by elastase, but was sensitive to both trypsin and chymotrypsin. In total, a series of sites of proteolysis were mapped, including R27, W52, Y59, K95, R96, and W100a (Kabat numbering). No sites of protease cleavage in the framework were found.Example 5: Engineering Anti-IL23R VHH Antibody Clone 2A8 to Increase Protease Resistance and Affinity2A8 was chosen to be further engineered for improved binding affinity and improved protease stability because this VHH had the highest inhibitory activity (FIG. 1), bound both human and cyno IL23R- Fc, and was the most protease stable VHH in pancreatin. A full domain saturation mutagenesis phage display library was generated to assess the contribution of each amino acid at every position within 2A8 with regard to both affinity and expression / folding. After several rounds of phage panning, the selected library and initial library were subject to next-generation sequencing and the enrichment ratio (round 3 frequency divided by input frequency) was calculated for every amino acid at every position. A heat map was generated indicating which mutations to 2A8 are compatible with folding of the VHH and high affinity binding to IL23R (FIG. 3).Using this dataset, mutations were engineered into 2A8 that would prevent proteolysis at the identified sites. First, 2A8 was humanized by grafting the CDRs onto the closet human germline (IGHV3- 23) along with key residues in the framework required for a soluble VHH (F37, E44, R45, F47, and A49; Kabat numbering). Two Vernier residues (D73 and V78; Kabat numbering) were determined to be required for maintaining parental binding affinity. With this humanized VHH, the next step was to make a trypsin-stable VHH. R27 was mutated to F to remove this site, which partially increased the trypsin stability (FIG. 4). A full domain scan showed that several other mutations (G and Y) at position 27 (Kabat numbering) would also remove this trypsin site and retain binding to IL23R. However, the heat map dataPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 and subsequent characterization of various mutations to either K95 or R96 revealed that K95 and R96 were critical for binding to IL23R. A V97P mutation (Kabat numbering) was identified, however, that could prevent trypsin cleavage after both K95 and R96 (FIG. 4). The combined mutant (R27F+V97P; v23) was fully trypsin-stable under these conditions and retained the binding affinity of the parental 2A8 antibody (FIG. 5A). The v23 variant also exhibited significantly improved stability out to 6 hours in pancreatin (FIG. 6). The v23 variant was also > 50% intact after 3 hours of incubation with elastase (FIG. 7).Next, the VHH antibody was modified to increase the chymotrypsin stability, because the pancreatin digestion experiments indicated clear VHH fragments with the trypsin-stable 2A8. Performing the protease cleavage site mapping experiment on v23 found that proteolysis occurred after only W52 and W100a (Kabat numbering). Proteolysis after Y59 (Kabat numbering) thus only occurs after cleavage at R27 or K95 / R96 (Kabat numbering). At W100a, the heat map indicated that no other amino acid was tolerated. To confirm, all 18 amino acid variants (except a cysteine variant) were generated, but binding to IL23R by SPR was not able to be detected. Surrounding residues (100b and 100c) were investigated to potentially protect this site from cleavage. Very few amino acid changes were tolerated at these positions. However, the addition of S100bD and S100bQ (Kabat numbering) to 2A8v23 significantly improved chymotrypsin stability as well as pancreatin stability (FIGS. 8 and 9). Moreover, the S1 OObQ variant of the parental 2A8 VHH antibody was stable in chymotrypsin (FIG. 5B). Overall, 2A8v23 with S1 OObQ (v82) resulted in the greatest stability enhancement and a 2-fold increase in affinity. These findings also indicate that W52 cleavage only occurs if W100a is first cleaved. Additionally, two bands were still observed on the SDS-PAGE gels, indicating proteolytic cleavage. MS analysis indicated that this cleavage was between the VHH and the C-terminal His tag. A tagless v82 was generated and it was demonstrated there was now -50% intact VHH after 20 hours of incubation (FIG. 10).Using the results of the saturation mutagenesis library, a series of 2A8 variants were next generated with individual and combinations of mutations to characterize by SPR and the protease stability assay, with the aim to improve the overall affinity of 2A8 without compromising the stability. Individual point mutations were made to the parental 2A8 VHH and found to mainly increase both affinity (as determined by measuring the off rate by SPR) and stability with the exception of three changes that showed no difference or a decrease in affinity or stability (Table 4 and FIG. 1 1 ).Table 4: Effect of single mutations on affinity and stability of 2A8 (His tagged VHH)PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Based on these results, sets of individual mutations were combined with the stabilizing mutations (v82: R27F, V97P, and S100bQ; Kabat numbering) with the goal of improving affinity and stability. These combinations of mutations and their effect on affinity and stability are outlined in Table 5 and FIG. 12. Surprisingly, it was found that while many of the mutants did increase affinity of v82, they also decreased the stability. In particular, A35S, A49G, and T57H (Kabat numbering) were found to decrease the stability of v82 in most cases. The addition of T64V and I69M (Kabat numbering) to v82 was found to increase both the affinity and stability (v123), and once this was combined with G98D (Kabat numbering), the most protease stable and highest affinity clone (v129) was obtained (FIG. 13).Table 5: Effect of combination mutations on affinity and stability of 2A8 (His-tagged VHH)Example 6: Engineering 2A8v129 to Exhibit Reduced Binding by Anti-Drug AntibodiesPrevious clinical data with VHHs has shown there that some patients possess pre-existing anti- VHH antibodies (Cordy et al. Clin Exp Immunol 2015; Holland et al. J Clin Immunol 2013; Papadopoulos et al. Cancer Chemother Pharmacol 2015). To mitigate any risk associated with binding to these preexisting antibodies, three mutations (T110Q, S112Q, and A114; Kabat numbering) were introduced into v129 to generate v134, which exhibited minimal binding of the pre-existing anti-VHH antibodies in 96 healthy donors (FIG. 14). FIG. 15 shows an alignment of v134 with 2A8, v23, v82, and v129.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Therefore, the clinical candidate v134 was the result of precise engineering to achieve high potency and protease stability. During the discovery and engineering process, four llamas were utilized, over 196 variants were generated, approximately 75 protein gels were run, and 10 mass spectrometry experiments were conducted. This process resulted in an exponential increase in IL23R affinity (KD) of the VHH antibodies from over 10 nM (2F1), to approximately 1 nM (v23), and to approximately 60 pM (v134) for both human and cyno IL23R. Importantly, the engineering achieved a prolonged pancreatin stability of the VHH antibodies from under 1 hour (2A8), to approximately 9 hours (v85), and to 20 hours (v134).Example 7: Characterization of Binding Affinity, Potency, and Stability of 2A8v129 and 2A8v134The binding affinities and stabilities of both v129 and v134 were measured to validate that these changes did not alter either property. Both VHHs bound to human and cyno IL23R with affinities of ~50 pM (Table 6). Both v129 and v134 exhibited improved stability to trypsin, chymotrypsin, and pancreatin (FIGS. 16-18).Table 6: Affinity of VHHs for human and cyno IL23R (untagged)IL23:IL23R Interaction Blocking by VHH 2A8v129 and2A8v134An in vitro assay was developed to directly measure the potency of inhibition of the p19:IL23R interaction. In this assay, a successful VHH competitor should prevent p19 / IL23 from binding to IL23R. Wash steps in the IL23:IL23R ELISA protocol (“ELISA with Washing Step” in Table 7) increase the stringency of the assay and allow detection of slow-off rate molecules.The ability of the 2A8v129 VHH to block the interaction between IL23 and IL23R was characterized using the biochemical IL23:IL23R blocking ELISA both with and without the washing step (FIGS. 19A, 19B, and Table 7). The 2A8v129 VHH exhibited similar potencies in both assay formats (without washing step and with washing step) with IC50s of 0.259 nM and 0.349 nM, respectively. Similar potencies were observed for the anti-IL23R IgG (m20D7; see, e.g., International Application Pub. No. WO 2008 / 106134, which is incorporated by reference herein in its entirety). Two comparator anti-IL23R peptides (26145 and 26149; see, e.g., U.S. Patent Application Pub. No. 2018 / 0022778, which is incorporated by reference herein in its entirety) were significantly less potent, with IC50s of approximately 27.5 nM without the washing step and >10,000 nM with the washing step. These results demonstrate that 2A8v129 VHH has potent IL23R affinity that interferes with IL23:IL23R interaction. The IL23R blocking ability of 2A8v134 VHH was also characterized in the biochemical ELISA with the washing step (FIG. 19C). The 2A8v134 VHH exhibited a potency of 0.14 nM compared to 0.15 nM for the m20D7 anti-IL23R IgG.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1Table 7: Inhibitory activity of anti-IL23R moleculesInhibition of IL23-induced IL 17F Secretion in Human PBMCsThe ability of the 2A8v134 VHH to inhibit IL23-mediated signaling in the primary T cell-based IL23R blockade assay was characterized by monitoring the production of IL17F in the presence and absence of the VHH (FIGS. 20A, 20B, and Table 8). The 2A8v134 VHH inhibited the production of IL17F with an IC50 of 6.835 nM, which was slightly better than the inhibition observed with the m20D7 monoclonal antibody (mAb), anti-IL23R IgG (7.7 nM). The anti-IL23R peptide 26149 showed very weak inhibition with an IC50 of 6757 nM. These data indicate that 2A8v134 anti-IL23R VHH potently inhibits IL23-induced IL17F secretion in primary human T cells.Table 8: Inhibitory activity of anti-IL23R moleculesHigh Protease Stability of2A8v134 in Physiologically Relevant MatricesThe protease stability of VHH 2A8v134 was measured in biological matrices, including mouse intestinal fluid (from the ileum, duodenum, jejunum, and cecum), mouse feces, and human feces. The in vitro protease cleavage assay (described in Example 1 ) with 5-10 mg / mL of pancreatin was used to measure pancreatin stability. Pooled mouse intestinal fluid was used in an in vitro protease cleavage assay to measure stability in mouse small intestine. Fecal samples were collected from mice that were orally gavaged with VHH and incubated for various times at 37°C. Resuspended human fecal samples were mixed with VHH and incubated for various times at 37°C. The amount of intact VHH was quantified by ELISA. VHH 2A8v134 demonstrated high stability in pancreatin (FIG. 20C), high stability in mouse intestinal fluid (FIG. 20D), high stability in mouse feces (FIG. 20E), and high stability in human feces (FIG. 20F). These data demonstrate high protease stability of VHH 2A8v134 in relevant biological matrices.Pharmocokinetic ELISAELISA plate preparation384-well Maxisorp plates (Nunc) were coated with hlL23R-Fc at a concentration of 2 pg / mL in PBS (25 pL per well). Plates were sealed and stored at 4 °C overnight. The following day, wells werePATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 washed 3x with wash buffer (PBS+0.05% TWEEN®20), and blocked using PBS+0.5% BSA (50 pL per well).Sample preparation and analysisSamples (may be mammalian-derived, for example, serum, SI contents, Peyer’s patches, fecal homogenate, urine, etc.) were diluted in sample buffer containing protease inhibitors (“Magic Buffer”+NaCI, No BgG containing complete ULTRA (Roche) at 20 tablets and 2 mM PMSF (Sigma) per 100 mL). Protease inhibitor is needed to prevent any proteases from the samples from affecting the IL23R-FC plate coating. Samples were diluted, initially and serially, to a range where matrix interference did not impact sample quantification. Anti-IL23R VHH (clone 2A8v134) was diluted to 10 ng / mL in sample buffer, and serially diluted 8 points, 1 :3x to use as a standard for sample quantification.ELISA protocolBlocked plates were washed 3x with wash buffer, and diluted samples and standards were subsequently added to the ELISA plate (25 pL per well). The plate was incubated for 2 hours with gentle agitation. After sample incubation, the plate was washed 6x with wash buffer, and diluted sheep anti-VHH (clone 22C5; heavy chain sequence of SEQ ID NO: 33 and the light chain sequence of SEQ ID NO: 32) diluted to 0.25 pg / mL in PBS+0.5% BSA+0.05% TWEEN®20 was added to each well (25 pL per well). The plate was then incubated for 1 hour with gentle agitation and subsequently washed 6x with wash buffer, followed by the addition of diluted goat anti-rabbit IgG-HRP (Jackson) at 1 :60,000 in PBS+0.5% BSA+0.05% TWEEN®20 (25 pL per well). After another hour of incubation with gentle agitation, the plate was again washed 6x with wash buffer, and Tetramethylbenzidine (Moss) (TMB), was added to each well (25 pL per well). The plate was incubated for 15 minutes with gentle agitation during development, and subsequently 1 M phosphoric acid (25 pL per well) was added to stop the reaction. The plate was briefly vortexed to ensure proper homogeneity of substrate and stop solution. ELISA plates were read on a monochromator plate reader (Thermo Multiskan Ascent) at a wavelength of 450 nm and a reference wavelength of 620 nm.Data Analysis MethodODs were processed using 5pt curve fitting (1 / Y weighting) of the VHH standard material (clone 2A8v134) to quantitate the amount of soluble 2A8v134 anti-IL23R VHH in each sample using the corresponding standard. Quantitated signal was corrected for dilution factor to reflect VHH content in source sample.Example 8: Methods for in vivo Characterization of anti-IL23R VHH AntibodiesThis example provides materials and methods for Examples 9-12, which characterize the in vivo characteristics of the anti-IL23R VHH antibodies disclosed herein.Pharmacokinetic Assay of Orally Inoculated VHH AntibodiesPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1For pharmacokinetics study, hlL23R ex3 knock-in mice were treated with 200 pL of 40% (w / v) of dextran sulfate sodium (DSS, colitis grade, MW. 36,000-50,000, MP Biomedicals) orally daily for 7 days to trigger colitis in the mice. The mice were then orally treated with 100 pL of gastroprotection solution (0.1 M sodium bicarbonate, and 400 g / L of non-fat dry milk). Fifteen minutes after administration of gastroprotection solution, the mice orally received 200 pL of 2.5 mg / mL VHH 2A8v134 in gastroprotection solution, or the same volume of gastroprotection solution. The mice were euthanized by cardiac puncture under anesthesia, and blood, mesenteric lymph nodes, small intestine, and colon were harvested for analysis.Development of Human IL23R Exon 3 Knock-In MouseHuman IL23 and anti-IL23R VHH antibody 2A8v134 bind to the D1 domain of hlL23R. According to the exon sequence alignment, the D1 domain is mainly coded on exon 3, and replacing mouse Il23r exon 3 with human IL23R exon 3 generates a chimeric IL23R with the human D1 domain. The construct for targeting the Il23r locus in C57BL / 6NTac C2 embryonic stem (ES) cells was generated through a combination of gene synthesis, recombineering, and standard molecular cloning techniques. The targeting vector contains human IL23R xon 3 surrounded by a 1830-bp 5’ homology arm and a 1903-bp 3’ homology arm with human IL23R exon 3 sequence. An FRT-PGK-em7-Neo-BGHpA-FRT cassette was inserted upstream of exon 3. The final vector was confirmed by DNA sequencing. The hlL23REx3 vector was linearized with Not I, C57BL / 6NTac C2 ES cells were targeted through standard methods (G418- positive and ganciclovir-negative selection), and positive clones were identified by PCR analysis. Correctly targeted ES cells were transfected with a Flp plasmid to remove Neo and generate the final hlL23Rex3 knock-in (KI) allele. Knock-in ES cells were then injected into blastocysts by standard techniques, and germline transmission was obtained after crossing the resulting chimeras with C57BL / 6N female mice.Pharmacodynamic Assay of Orally Inoculated VHH Molecule in Exogenous IL23 Injection Model Human IL23R ex3 knock-in mice were treated with 3% (w / v) of DSS in drinking water for 7 days, and back to regular drinking water. VHH molecules were engineered for protease resistance and increased affinity, but they were still susceptible to pepsin digestion in stomach. To protect orally inoculated VHH molecules during transit through stomach, the mice were orally pre-treated with 100 pL gastroprotection solution containing sodium bicarbonate and milk. Fifteen minutes later, the mice orally received 200 pL of 0.4, 1 .0, or 2.5 mg / mL VHH 2A8v134 in gastroprotection solution, or the same volume of gastroprotection solution. This treatment was repeated at -18, -3 and 0 hours. Then, at time 0, on day 9, the mice received intravenously 100 pL of 0.2 mg / mL of human IL23 (Genentech). After 3 hours, the mice were euthanized by cardiac puncture under anesthesia, and blood, mesenteric lymph nodes, spleen, ileum, and colon were harvested for analysis.Pharmacodynamic Assay of Orally Inoculated VHH Molecule in Anti-CD40-lnduced Colitis Model Human IL23R ex3 knock-in mice were crossed with Rag2 knock-out mice to generate mice expressing chimeric IL23R in a Rag2 knock-out background. The mice were treated with 1 .5% (w / v) ofPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1DSS in the drinking water for 6 days. Four days after starting DSS treatment, mice received 100 |_il_ of 2 mg / mL anti-CD40 (Genentech) intravenously. Two days later, mice start receiving oral inoculation of VHH 2A8v134 3 times a day for 4 days. For each treatment, the mice were orally treated with 100 |_il_ of gastroprotection solution. Fifteen minutes later, the mice orally received 200 pL of 10 mg / mL VHH 2A8v134 in gastroprotection solution, or the same volume of gastroprotection solution. Three and 5 days after the anti-CD40 treatment, mice also received 200 pL of 1 mg / mL of anti-hlL23R IgG (m20D7) intraperitoneally. Six days after the anti-CD40 treatment, the mice were euthanized by cardiac puncture under anesthesia, and blood, mesenteric lymph nodes, spleen, ileum, and colon were harvested for analysis.Cynomolgus Monkey StudyCambodian cynomolgus monkey are orally inoculated with enteric coated capsule containing mini-tablets of spray-dried VHH 2A8v134, or vehicle control, on day 0, and blood samples were harvested at 2, 4, 8, 24, and 48 h. Then the same animals were orally inoculated again with VHH pill or control pill daily from day 4 to day 7. The blood and fecal samples were harvested at 4 h on day 4. On day 7 at 8 h after the final oral inoculation, the animals were euthanized and blood, Gl tract and Gl contents were harvested. Fecal samples were harvested from the cage.The serum PK and rectum content PK were predicted by a physiological based pharmacokinetic modeling and simulation approach (PBPK). That PBPK model accounts for the Weibull distribution function to simulate the VHH distribution in the small intestine, the VHH transition following the physiologically relevant Gl transit time, and VHH absorption depending on regional surface area. In addition, the potential VHH degradation in colon fluid was considered in the PBPK model to simulate the rectum content PK.Mouse Tissue ProcessingBlood samples were collected in serum separator (Sarstedt) and spun at 12,000 rpm for 10 min at 4°C for serum separation, and the cytokine level was analyzed by Luminex (Millipore Premix Th 1725- plex).For the pharmacokinetics and IHC assay, small intestine and colon samples were harvested in 10% neutral buffered formalin. Tissues were sectioned and stained with anti-VHH framework monoclonal antibody 20E5 (heavy chain sequence of SEQ ID NO: 43 and the light chain sequence of SEQ ID NO: 42). Tissue samples were homogenized using TissueLyser (Eppendorf) with beads, in PBS containing proteinase inhibitor (Roche) and PMSF (Sigma), and centrifuged at 14,000 rpm for 5 min at 4°C. Supernatants were analyzed for VHH concentration by ELISA detecting only functional VHH.For the pharmacodynamics assay, the mesenteric lymph nodes, ileum, and colon samples were incubated in RNAIater (Ambion, Thermo Fisher Scientific), and homogenized in Trizol reagent (Invitrogen, Thermo Fisher Scientific) by GentleMax (Miltenyi). After chloroform extraction, RNA was further purified by the RNeasy kit (Qiagen) with on-column DNase treatment (Qiagen), according to the manufacturer’s instructions. Isolated RNAs were reverse-transcribed with Superscript Vilo master mix (Invitrogen, Thermo Fisher Scientific) according to the manufacturer’s instructions, and analyzed for gene expressionPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 by a real-time PCR system (Applied Biosystems, Thermo Fisher Scientific), using the following oligonucleotides, and mouse / / 77f (Mm00521423_m1 , Applied Biosystems, Thermo Fisher Scientific). / / 22 forward: 5’-TCC GAG GAG TCA GTG CTA A-3’ (SEQ ID NO: 18) reverse: 5-AGA ACG TOT TOO AGG GTG AA-3’ (SEQ ID NO: 19) probe: 5 -FAM-TGA GCA OCT GOT TCA TCA GGT AGC A-TAMRA-3’ (SEQ ID NO: 20)Rpl19 forward: 5-GCA TCC TCA TGG AGC ACA T-3’ (SEQ ID NO: 21) reverse: 5-CTG GTC AGC CAG GAG CTT-3’ (SEQ ID NO: 22) probe: 5 -FAM-CTT GCG GGC CTT GTC TGC CTT-TAMRA-3’ (SEQ ID NO: 23)Data were analyzed using GraphPad Prism 6 software. Student's t-tests were performed for statistical analyses.Phospho-STATS Assay with Human Whole Blood and Cynomolgus MonkeyWhole blood from a healthy donor was incubated with either VHH 2A8v134 or control antibody at a final concentration of 5 pg / mL for 30 min at 37°C. After incubation with human IL23 at the final concentration of 50 ng / mL for another 30 min at 37°C, pre-warmed RBC Lysis / Fixation buffer (BioLegend) was added, and incubated for another 15 min at 37°C. After washing twice with FACS buffer (PBS containing 2% FBS and 0.2% NaNs), the cells were resuspended in True-Phos Perm buffer (BioLegend) and incubated over night at -20°C. The next day, the cells were washed twice with FACS buffer, incubated in 50% human serum / FACS buffer for 20 min at room temperature, and stained with anti- hCD45RO-PE (BD), anti-hCD4-FITC (BD), and anti-phospho-STAT3 Y705-Alexa Fluor 647® (BioLegend) for 30 min. For cynomolgus monkey blood samples, the cells were stained by anti-hCD3e-FITC (BD) and anti-phospho-STAT3 Y705-Alexa Fluor 647 (BioLegend). After washing twice with FACS buffer, the cells were analyzed by BD Symphony (BD). The data were analyzed by FlowJo (BD).Trans-well AssayA monolayer of human colonic epithelial cells was generated on a trans-well plate according to the manufacturer’s protocol (Altis Biosystems, RepliGut). After the monolayer was formed on the trans- well, the cells were differentiated for 8 days, and then treated with IFN-y, TNF-a or both at 100 ng / mL. TEER was measured prior to and 24 h after the addition of cytokines. 10 pg / mL of VHH 2A8v134 was supplied on the upper chamber at 24 h after the cytokine treatment, and the medium was harvested from the lower chamber 24 h later for the analysis.Example 9: Pharmacokinetics of Anti-IL23R VHH AntibodiesAnti-IL23R VHH binds to human and cynomolgus monkey IL23 receptor but not mouse or rat. To test the ability of anti-hlL23R VHH molecules to inhibit hlL23 signaling in vivo, human IL23R exon 3PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1 knock-in mice were generated. In separate studies, hlL23 p19 subunit was found to directly interact with D1 domain of hlL23R, and VHH 2A8v134 was also found to bind the same domain. The majority of the D1 domain is coded in exon 3, and only the last 3 amino acids are coded in exon 4. Since this 3-amino acid sequence is conserved between human and mouse, the knocking-in of human exon 3 is sufficient to humanize mouse D1 domain to allow cytokine and VHH binding. We have confirmed with in vitro assays that such a mouse IL23R receptor with the human D1 domain is functional and responsive to human and mouse IL23 activation in a dose-dependent manner, and that the activation by IL23 can be blocked by anti-hlL23R IgG antibody and VHH.Pharmacokinetic Assay of Orally Inoculated VHH MoleculeTo evaluate whether VHH molecules can enter into tissue, a pharmacokinetics assay in hlL23R ex3 knock-in mice was performed. The aim was to evaluate how VHH molecules enter into tissue and quantify VHH in tissue and the systemic circulation using an ELISA assay that only measures active VHH. Dextran sodium sulfate (DSS) is commonly used to induce experimental colitis through chemical injury of the colonic epithelial layer. Mice were fed with DSS in drinking water for 7 consecutive days to induce experimental colitis with diarrhea and epithelial inflammation. VHH molecules were engineered for intestinal and colonic protease resistance and increased affinity; however, they were still susceptible to pepsin digestion in the acidic environment of the stomach. For cynomolgus studies, an enteric-coated capsule can be used to bypass the stomach and to release the active drug content in the small intestine. Such capsules, due to the large pill size, are not compatible with mouse studies. To mitigate such challenges, mice were pre-treated with gastroprotection solution containing 0.1 M sodium bicarbonate and 400 mg / mL milk. Thirty minutes after pretreatment with gastroprotection solution, 500 pg of VHH was orally inoculated, and the tissue distribution of VHH was evaluated.As shown in FIG. 21 A, VHH was detected in the small intestine and colon by immunohistochemistry with the anti-VHH framework monoclonal antibody. Moreover serum and tissue homogenate of ileum and colon showed detectable VHH, whereas mice with intact epithelial layer (no DSS) showed much lower concentrations of VHH. As shown in FIGS. 21 B and 21 C, a significantly increased VHH concentration in the serum and urine of DSS colitis mice was observed compared with the naive healthy mouse control. Consistent with the increased systemic concentration, VHH was elevated in mesenteric lymph nodes, Peyer’s patches, and colon of the colitis mice compared to naive healthy mice (FIGS. 21 D, 21 E, and 21 G). There was no difference between DSS-treated or untreated animals in ileum tissues (FIG. 21 F), which is consistent with histopathological findings that DSS treatment induces only epithelial inflammation and injury in colon, but not in small intestine. Individual pharmacokinetic data for VHH 2A8v134 in the small intestine and colon are also described for mice treated with or without DSS (FIG. 21 H).The penetration of VHH through the gut epithelium was further validated by immunohistochemistry staining using an anti-VHH framework monoclonal antibody. VHH immunohistochemistry staining was performed to visualize VHH tissue pharmacokinetics and which cell types take up VHH. In healthy mouse colon, VHH 2A8v134 mostly adhered to the mucus layer, with spotty uptake by mucin-producing goblet cells. Also, in the healthy small intestine, VHH was taken up andPATENTAttorney Docket No.: 50474-371 WO2 Genentech Docket No.: P39717-WO-1 transcytosed by goblet cells and Paneth cells. Both goblet cells and Paneth cells have been reported to sample the lumen protein into lamina propria. In colitic colonic tissue, significant VHH staining intensity was detected at the lamina propria, especially in the region with epithelial lesions. The signal was higher around the lesion, compared to the intact area, indicating that the VHH tends to penetrate through the intestinal epithelium where the tight junctions and epithelial lining are compromised. These findings corroborate that VHH can penetrate into target tissues such as colon and ileum if the epithelial layer is damaged.Trans-well Assay Showed Loss of Monolayer Integrity and Increased PermeabilityThe in vivo pharmacokinetic analysis was also supported by the in vitro trans-well assay, in which human colonic epithelial monolayers on a trans-well membrane were treated with proinflammatory cytokines such as IFNy and TNFa. Using cytokine treatment, cell death was promoted and the integrity of the monolayer was disrupted, causing permeability of VHH into the epithelium (FIGS. 211 and 21 J). Histopathological analysis of the transwell cells showed that TNFa or IFNy promoted permeability by disturbing tight junctions but the combination of both cytokines induced epithelial cell...

Claims

PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1WHAT IS CLAIMED IS:1 . An isolated VHH antibody that specifically binds interleukin-23 receptor (IL23R), wherein the VHH antibody comprises a binding domain comprising the following complementarity-determining regions (CDRs):(a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1), wherein Xi is A or S;(b) a ODR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2 is G or D; and(c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V.

2. The VHH antibody of claim 1 , wherein the binding domain comprises:(a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4);(b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1G (SEQ ID NO: 5), wherein Xi is V or T; and(c) a CDR-H3 comprising the amino acid sequence of KRPX1AGWX2TYDY (SEQ ID NO: 6), wherein Xi is D or G, and X2 is Q, S, or D.

3. The VHH antibody of claim 1 or 2, wherein the binding domain comprises:(a) a CDR-H1 comprising the amino acid sequence of TYAMA (SEQ ID NO: 4);(b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVVG (SEQ ID NO: 7); and(c) a CDR-H3 comprising the amino acid sequence of KRPDAGWQTYDY (SEQ ID NO: 8).

4. The VHH antibody of any one of claims 1 -3, wherein the binding domain comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMAWFRQAPGKEREFVAESWSSGTTYYGASVVGRFT MSRDDSKNTVYLQMNSLRAEDTAVYYCAAKRPDAGWQTYDYWGQGTLVQVQSA (SEQ ID NO: 9).

5. The VHH antibody of any one of claims 1 -4, wherein the binding domain comprises an amino acid sequence having no more than six addition, substitution, and / or deletion mutations compared to SEQ ID NO: 9.

6. The VHH antibody of any one of claims 1 -5, wherein the binding domain comprises the following framework regions (FRs):(a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQX1GX2SLRLSCAASGX3TFS (SEQ ID NO: 10), wherein Xi is P or L, X2 is G or D, and X3 is F, G, Y, or R;(b) an FR-2 comprising the amino acid sequence of WFRQAPGKEREFVA (SEQ ID NO: 11);(c) an FR-3 comprising the amino acid sequence of RFTX1SRDDX2KNTVYLQMNSLX3X4EDTAVYYCAA (SEQ ID NO: 12), wherein Xi is M or I, X2is S or A, X3 is R or K, and X4 is A or P; andPATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1(d) an FR-4 comprising the amino acid sequence of WGQGTLVX1VX2S (SEQ ID NO: 13), wherein Xi is Q or T and X2 is Q or S.

7. The VHH antibody of any one of claims 1 -6, wherein the binding domain comprises the following FRs:(a) an FR-1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 14);(b) an FR-2 comprising the amino acid sequence of WFRQAPGKEREFVA (SEQ ID NO: 11);(c) an FR-3 comprising the amino acid sequence of RFTMSRDDSKNTVYLQMNSLRAEDTAVYYCAA (SEQ ID NO: 15); and(d) an FR-4 comprising the amino acid sequence of WGQGTLVQVQS (SEQ ID NO: 16).

8. The VHH antibody of any one of claims 1 -7, wherein the binding domain comprises a Q at position 110, a Q at position 1 12, and a C-terminal addition of an A at position 114 (Kabat numbering).

9. The VHH antibody of any one of claims 1 -8, wherein the binding domain comprises the amino acid sequence of SEQ ID NO: 9.

10. The VHH antibody of claim 9, wherein the binding domain consists of the amino acid sequence of SEQ ID NO: 9.11 . An isolated VHH antibody that specifically binds IL23R, wherein the VHH antibody comprises a binding domain comprising the amino acid sequence of SEQ ID NO: 9.

12. The VHH antibody of any one of claims 1 -1 1 , wherein the VHH antibody specifically binds human or cynomolgus (cyno) IL23R.

13. The VHH antibody of any one of claims 1 -12, wherein the VHH antibody specifically binds both human and cyno IL23R.

14. The VHH antibody of any one of claims 1 -13, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD of about 1 nM or lower.

15. The VHH antibody of any one of claims 1 -14, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD between about 100 fM and about 1 nM.

16. The VHH antibody of any one of claims 1 -15, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD between about 750 fM and about 300 pM.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-117. The VHH antibody of any one of claims 1 -16, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD between about 1 pM and about 200 pM.

18. The VHH antibody of any one of claims 1 -17, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM.

19. The VHH antibody of any one of claims 1 -18, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD of about 60 pM.

20. The VHH antibody of any one of claims 14-19, wherein the KD is measured by a surface plasmon resonance assay at 37°C.21 . The VHH antibody of any one of claims 1 -20, wherein the VHH antibody inhibits binding of IL23 to IL23R.

22. The VHH antibody of claim 21 , wherein the VHH antibody inhibits binding of IL23 to IL23R as determined by a cell-based functional assay.

23. The VHH antibody of any one of claims 1 -22, wherein the VHH antibody is at least partially resistant to proteolysis by one or more proteases.

24. The VHH antibody of claim 23, wherein the one or more proteases are elastase, trypsin, or chymotrypsin.

25. The VHH antibody of claim 23, wherein the VHH antibody is at least partially resistant to proteolysis by elastase, trypsin, and chymotrypsin.

26. The VHH antibody of any one of claims 23-25, wherein at least about 5% of an initial amount of the VHH antibody is intact after at least one hour of exposure to elastase, trypsin, chymotrypsin, or pancreatin.

27. The VHH antibody of any one of claims 23-26, wherein at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to pancreatin.

28. The VHH antibody of any one of claims 23-27, wherein at least about 50% of an initial amount of the VHH antibody is intact after at least 20 hours of exposure to pancreatin.

29. The VHH antibody of any one of claims 23-28, wherein at least about 50% of an initial amount of the VHH antibody is intact after at least 3 hours of exposure to elastase.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-130. The VHH antibody of any one of claims 23-29, wherein at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to trypsin.31 . The VHH antibody of any one of claims 23-30, wherein at least about 50% of an initial amount of the VHH antibody is intact after at least 4 hours of exposure to chymotrypsin.

32. The VHH antibody of any one of claims 23-31 , wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.

33. The VHH antibody of claim 32, wherein the in vitro protease stability assay uses pancreatin at a concentration of 10 mg / mL, elastase at a concentration of 1000 pg / mL, trypsin at a concentration of 500 pg / mL, and / or chymotrypsin at a concentration of 100 pg / mL.

34. The VHH antibody of any one of claims 1 -33, wherein the VHH antibody is a humanized or chimeric antibody.

35. The VHH antibody of any one of claims 1 -34, wherein the VHH antibody is a full-length antibody.

36. The VHH antibody of any one of claims 1 -34, wherein the VHH antibody is a VHH antibody fragment that specifically binds IL23R.

37. The VHH antibody of any one of claims 1 -34 and 36, wherein the VHH antibody is a VHH singledomain antibody.

38. The VHH antibody of any one of claims 1 -37, wherein the VHH antibody is not significantly bound by pre-existing anti-VHH antibodies in a subject.

39. The VHH antibody of claim 38, wherein the subject is a human.

40. The VHH antibody of any one of claims 1 -39, wherein the VHH antibody specifically binds to an epitope in the D1 domain of human IL23R.41 . The VHH antibody of any one of claims 1 -40, wherein the VHH antibody comprises an Fc region.

42. The VHH antibody of claim 41 , wherein the Fc region is an IgG Fc region.

43. The VHH antibody of claim 41 or 42, wherein the Fc region or IgG Fc region is human.

44. The VHH antibody of any one of claims 41 -43, wherein the amino terminus of the Fc region is fused to the carboxy terminus of the binding domain of the VHH antibody.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-145. The VHH antibody of any one of claims 1 -44, wherein the binding domain of the VHH antibody is fused to a anti-serum albumin antibody.

46. The VHH antibody of claim 45, wherein the anti-serum albumin antibody is human.

47. An isolated VHH antibody that specifically binds to the same epitope on IL23R that is bound by a VHH antibody comprising a binding domain comprising the following complementarity-determining regions (CDRs):(a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1), wherein Xi is A or S;(b) a ODR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2 is G or D; and(c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V.

48. An isolated VHH antibody that competes for binding with a VHH antibody comprising a binding domain comprising the following complementarity-determining regions (CDRs):(a) a CDR-H1 comprising the amino acid sequence of TYAMXi (SEQ ID NO: 1), wherein Xi is A or S;(b) a CDR-H2 comprising the amino acid sequence of ESWSSGTTYYGASVX1X2 (SEQ ID NO: 2), wherein Xi is V or T, and X2 is G or D; and(c) a CDR-H3 comprising the amino acid sequence of KRX1X2AGWX3X4YDY (SEQ ID NO: 3), wherein Xi is P or V, X2 is D or G, X3 is Q, S, or D, and X4 is T or V.

49. An immunoconjugate comprising the VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R.

50. An isolated nucleic acid encoding the VHH antibody of any one of claims 1-48.51 . A vector comprising the isolated nucleic acid of claim 50.

52. A host cell comprising the vector of claim 51 .

53. The host cell of claim 52, wherein the host cell is a eukaryotic cell.

54. The host cell of claim 53, wherein the eukaryotic cell is a mammalian cell.

55. The host cell of claim 54, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell.

56. The host cell of claim 52, wherein the host cell is a prokaryotic cell.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-157. The host cell of claim 56, wherein the prokaryotic cell is Escherichia coli.

58. A method of producing a VHH antibody that specifically binds to IL23R, the method comprising culturing the host cell of any one of claims 52-57 in a culture medium under conditions that are suitable for producing the VHH antibody.

59. The method of claim 58, wherein the method further comprises recovering the VHH antibody from the host cell or the culture medium.

60. A composition comprising the VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R.61 . The composition of claim 60, further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

62. The composition of claim 61 , wherein the composition is a pharmaceutical composition.

63. The composition of any one of claims 60-62, wherein the composition is formulated for oral administration.

64. The composition of any one of claims 60-63, wherein the composition comprises one or more minitablets.

65. The composition of claim 64, wherein the one or more minitablets each comprises the VHH antibody.

66. The composition of claim 64 or 65, wherein the one or more minitablets are formulated to deliver a total dose of 150 mg of the VHH antibody.

67. The composition of claim 64 or 65, wherein the one or more minitablets are formulated to deliver a total dose of 300 mg of the VHH antibody.

68. The composition of any one of claims 64-67, wherein the one or more minitablets comprise mannitol.

69. The composition of claim 68, wherein the one or more minitablets comprise mannitol at a ratio of 5 mg of the VHH antibody to 1 mg of mannitol.

70. The composition of any one of claims 64-69, wherein the one or more minitablets comprise histidine.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-171 . The composition of any one of claim 70, wherein the one or more minitablets comprise histidine hydrochloride.

72. The composition of any one of claims 64-71 , wherein the one or more minitablets are seal coated.

73. The composition of any one of claims 64-72, wherein the one or more minitablets are enteric coated.

74. The composition of any one of claims 64-73, wherein the one or more minitablets are formulated as a suspension in medium.

75. The composition of claim 74, wherein the medium has a pH of about 3.5.

76. The composition of any one of claims 64-75, wherein the one or more minitablets are formulated in a capsule.

77. The composition of claim 76, wherein the capsule is not coated.

78. The VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R, or the composition of any one of claims 60-77 for use as a medicament.

79. The VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R, or the composition of any one of claims 60-77 for use in treating or delaying a gastrointestinal-related (Gl- related) disease.

80. The VHH antibody or fragment thereof or composition for use of claim 79, wherein the Gl-related disease is an inflammatory bowel disease (IBD), a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation.81 . The VHH antibody or fragment thereof or composition for use of claim 80, wherein the Gl-related disease is an IBD.

82. The VHH antibody or fragment thereof or composition for use of claim 80 or 81 , wherein the IBD is ulcerative colitis or Crohn’s disease.

83. The VHH antibody or fragment thereof or composition for use of claim 82, wherein the IBD is ulcerative colitis.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-184. The VHH antibody or fragment thereof or composition for use of claim 83, wherein the ulcerative colitis is moderate to severe ulcerative colitis.

85. The VHH antibody or fragment thereof or composition for use of claim 82, wherein the IBD is Crohn’s disease.

86. The VHH antibody or fragment thereof or composition for use of claim 80, wherein the gut- associated infection is a Salmonella infection or Clostridium difficile infection.

87. Use of the VHH antibody of any one of claims 1 -48 or the composition of any one of claims 60-77 in the manufacture of a medicament for treating a Gl-related disease.

88. The use of claim 87, wherein the Gl-related disease is an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation.

89. The use of claim 88, wherein the Gl-related disease is an IBD.

90. The use of claim 88 or 89, wherein the IBD is ulcerative colitis or Crohn’s disease.91 . The use of claim 90, wherein the IBD is ulcerative colitis.

92. The use of claim 91 , wherein the ulcerative colitis is moderate to severe ulcerative colitis.

93. The use of claim 90, wherein the IBD is Crohn’s disease.

94. The use of claim 88, wherein the gut-associated infection is a Salmonella infection or Clostridium difficile infection.

95. A method for treating or delaying progression of a Gl-related disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the VHH antibody of any one of claims 1 -48 or the composition of any one of claims 60-77.

96. The method of claim 95, wherein the Gl-related disease is an IBD, a colon cancer, a small intestine cancer, a gastric cancer, an irritable bowel syndrome, a gastrointestinal ulcer, a gut-associated infection, celiac disease, or pathogenic inflammation.

97. The method of claim 96, wherein the Gl-related disease is an IBD.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-198. The method of claim 96 or 97, wherein the IBD is ulcerative colitis or Crohn’s disease.

99. The method of claim 98, wherein the IBD is ulcerative colitis.

100. The method of claim 99, wherein the ulcerative colitis is moderate to severe ulcerative colitis.101 . The method of claim 98, wherein the IBD is Crohn’s disease.

102. The method of claim 96, wherein the gut-associated infection is a Salmonella infection orClostridium difficile infection.

103. The method of any one of claims 95-102, wherein the VHH antibody or the composition is administered orally, intrarectally, mucosally, intravenously, intramuscularly, intradermally, transdermally, subcutaneously, percutaneously, intraarterially, intraperitoneally, intravitreally, topically, intralesionally, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intratumorally, intraperitoneally, peritoneally, intraventricularly, intracranially, subconjunctivally, intravesicu larly, intrapericardially, intraumbilically, intraorbital ly, ocularly, intraocu larly, juxtascleral ly, subtenonly, superchoroidally, by inhalation, by injection, by eye drop, by implantation, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.

104. The method of any one of claims 95-103, wherein the VHH antibody or the composition is administered orally.

105. The method of any one of claims 95-104, wherein the subject is a human.

106. A method of detecting human IL23R in a biological sample comprising contacting the biological sample with the VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R, or the immunoconjugate of claim 49 under conditions permissive for binding of the VHH antibody or immunoconjugate to a naturally occurring human IL23R, and detecting whether a complex is formed between the VHH antibody or immunoconjugate and the naturally occurring human IL23R.

107. A kit comprising the VHH antibody of any one of claims 1 -48, or a fragment thereof that specifically binds IL23R, the immunoconjugate of claim 49, or the composition of any one of claims 60-77 and a package insert comprising instructions for treating or delaying a Gl-related disease.

108. A VHH antibody or fragment thereof that specifically binds IL23R, wherein the antibody has at least one of the following characteristics:(a) specifically binds human IL23R and cynomolgus (cyno) IL23R;PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1(b) specifically binds both human and cyno IL23R with a KD of about 1 nM or lower, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(c) specifically binds both human and cyno IL23R with a KD between about 100 fM and about 1 nM, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(d) specifically binds both human and cyno IL23R with a KD between about 750 fM and about 300 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(e) specifically binds both human and cyno IL23R with a KD between about 1 pM and about 200 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(f) specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(g) inhibits binding of IL23 to IL23R as determined by a cell-based functional assay;(h) is at least partially resistant to proteolysis by pancreatin or one or more of elastase, trypsin, or chymotrypsin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C;(i) at least about 5% of about 10-15 pg of the VHH antibody is intact after at least one hour of exposure to elastase, trypsin, chymotrypsin, or pancreatin, wherein the pancreatin is at a concentration of about 10 mg / mL, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C;(j) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 4 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C;(k) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; or(l) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.

109. The VHH antibody of claim 108, wherein the VHH antibody specifically binds both human and cyno IL23R with a KD of about 60 pM, and wherein the KD is measured by a surface plasmon resonance assay at 37°C.

110. The VHH antibody of claim 108, wherein the VHH antibody specifically binds both human and cyno IL23R, wherein at least about 50% of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.

111. The VHH antibody of claim 110, wherein at least about 50% of 10-15 pg of the antibody is intact.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1112. The VHH antibody of claim 111 , wherein the pancreatin is at a concentration of about 10 mg / mL113. The VHH antibody of claim 108, wherein the VHH antibody specifically binds both human and cyno IL23R, wherein at least about 50% of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, and wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.

114. The VHH antibody of claim 113, wherein at least about 50% of 10-15 pg of the VHH antibody is intact.

115. The VHH antibody of claim 108, which has the following characteristics:(a) specifically binds human IL23R and cynomolgus (cyno) IL23R;(b) specifically binds both human and cyno IL23R with a KD between about 20 pM and about 100 pM, wherein the KD is measured by a surface plasmon resonance assay at 37°C;(c) inhibits binding of IL23 to IL23R as determined by a cell-based functional assay;(d) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 20 hours of exposure to pancreatin, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C; or(e) at least about 50% of about 10-15 pg of the VHH antibody is intact after at least 3 hours of exposure to elastase at about 1000 pg / mL, or after at least 4 hours of exposure to trypsin at about 500 pg / mL or chymotrypsin at about 100 pg / mL, wherein resistance to proteolysis is determined by an in vitro protease stability assay at 37°C.

116. The VHH antibody of any one of claims 108-115, wherein the VHH antibody is a humanized or chimeric antibody.

117. The VHH antibody of any one of claims 109-115, wherein the VHH antibody is a full-length antibody.

118. The VHH antibody of any one of claims 109-115, wherein the VHH antibody is a VHH antibody fragment that specifically binds IL23R.

119. The VHH antibody of any one of claims 109-115 and 118, wherein the VHH antibody is a VHH single-domain antibody.

120. The VHH antibody of any one of claims 109-119, wherein the VHH antibody is not significantly bound by pre-existing anti-VHH antibodies in a subject.121 . The VHH antibody of claim 120, wherein the subject is a human.PATENTAttorney Docket No.: 50474-371 WO2Genentech Docket No.: P39717-WO-1122. The VHH antibody of any one of claims 108-121 , wherein the VHH antibody specifically binds to an epitope in the D1 domain of human IL23R.

123. The VHH antibody of any one of claims 108-122, wherein the VHH antibody comprises an Fc region.

124. The VHH antibody of claim 123, wherein the Fc region is an IgG Fc region.

125. The VHH antibody of claim 123 or 124, wherein the Fc region or IgG Fc region is human.

126. The VHH antibody of any of claims 123-125, wherein the amino terminus of the Fc region is fused to the carboxy terminus of the binding domain of the VHH antibody.

127. The VHH antibody of any one of claims 108-126, wherein the binding domain of the VHH antibody is fused to a anti-serum albumin antibody.

128. The VHH antibody of claim 127, wherein the anti-serum albumin antibody is human.

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