Antibodies to il21r and compositions thereof

Abstract

The present disclosure provides antibodies that bind to IL21R, and methods of using them to modulate immunity in a patient in need thereof and to treat autoimmune disorders or immunoinflammatory disorders.

Description

ANTIBODIES TO IL21R AND COMPOSITIONS THEREOFSEQUENCE LISTING

[0001] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 5, 2026, is named 027628_P1012_SL.xml and is 137,718 bytes in size.BACKGROUND OF THE INVENTION

[0002] Interleukin 21 receptor (IL21R) is a heterodimeric complex composed of a common gamma chain (IL-2Ry or CD 132) and a specific IL21 receptor chain (IL21Ra or CD360), and belongs to the family of receptors for type I cytokines that also include IL2, IL4, IL7, IL9, and IL15. IL21R is expressed on a variety of immune cells, including B cells, dendritic cells (DCs), natural killer (NK) cells, macrophages, and T cells. Upon forming a heterodimeric receptor complex with the common gamma chain (yc), IL21R binds to its ligand, interleukin 21 (IL21) which is produced mainly by CD4+T cells and NK T cells (NKT). The IL21R-IL21 interaction is involved in several signaling pathways, including the Jak / STAT pathway. IL21 signaling can activate STAT1, STAT3, and both STAT5a and STAT5b; IL-21 -specific biological effects are mostly driven by the activation of STAT3. The phosphoinositide 3 -kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways also contribute to IL-21 signaling and are involved in IL-21 -dependent effects on cell survival and proliferation. IL21R signaling plays a role in the proliferation, differentiation, and activity of immune cell types including T cells, B cells, and NK cells.

[0003] While IL21R has a central role in generating effective immune responses, it also has a pathogenic role in several autoimmune and inflammatory disorders. The IL21 signaling pathway has been implicated in, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), immune thrombocytopenia (ITP), Type 1 diabetes, inflammatory bowel disease (IBD), autoimmune thyroid disease (AITD), psoriasis, multiple sclerosis (MS), Sjogren’s syndrome, vitiligo, and pemphigus, among others.

[0004] ATR-107 is an anti-IL21R antibody derived from a parental clone 18A5(WO 2004 / 083249 Al; WO 2009 / 143526; Vugmeyster et al., 2010, mAbs 2:3, 335-346), and the only one anti-IL21R antibody that underwent clinical trial. Clinical development washowever discontinued after phase I clinical trial due to immunogenicity and elicitation of anti-drug antibodies (Xue et al., 2016, Clin Exp Immunol. , 183(1): 102-13).

[0005] In view of the role of IL21R in immune responses and their repercussions in autoimmune and immunoinflammatory disorders, there is a need for new and improved therapies that target IL21R.SUMMARY OF THE INVENTION

[0006] The present disclosure provides anti-IL21R antibodies and antigen-binding portions thereof. The anti-IL21R antibody or antigen-binding portion of the present disclosure may be antagonistic and block the binding of IL21 to IL21R. In certain embodiments, an anti-IL21R antibody or antigen-binding portion herein binds specifically to one or more of amino acids D53, Q54, Y55, E56, E57, H87, F88, M89, A90, D91, 193, Sill, LI 13, Al 15, El 16, and S209 of SEQ ID NO: 57, for example to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all 16 of said amino acids. In particular embodiments, an anti-IL21R antibody or antigen-binding portion herein binds specifically to one or more of amino acids D53, Y55, E56, H87, D91, SI 11, and El 16 of SEQ ID NO: 57, for example to 3, 4, 5, 6, or all 7 of said amino acids. In particular embodiments, an anti-IL21R antibody or antigen-binding portion herein binds specifically to all of amino acids D53, Y55, E56, H87, D91, Sill, and El 16 of SEQ ID NO: 57. In particular embodiments, an anti-IL21R antibody or antigen-binding portion herein binds specifically to all of amino acids D53, Q54, Y55, E56, E57, H87, F88, M89, A90, D91, 193, Sill, LI 13, Al 15, El 16, and S209 of SEQ ID NO: 57.

[0007] In some embodiments, the present disclosure provides an isolated anti-IL21R antibody or an antigen-binding portion thereof, wherein the antibody binds to the same epitope as a reference antibody having a heavy chain variable domain (VH) and a light chain variable domain (VL) comprisingSEQ ID NOs: 1 and 2, respectively,SEQ ID NOs: 11 and 12, respectively,SEQ ID NOs: 21 and 22, respectively,SEQ ID NOs: 31 and 32, respectively,SEQ ID NO: 90 and 91, respectively,SEQ ID NO: 96 and 97, respectively,SEQ ID NO: 101 and 102, respectively,SEQ ID NO: 104 and 105, respectively,SEQ ID NO: 108 and 109, respectively, orSEQ ID NO: 112 and 113, respectively.

[0008] In some embodiments, the heavy chain of the anti-IL21R antibody comprises: i) heavy chain complementarity determining regions (HCDR) 1-3 comprising SEQ ID NOs: 3-5, respectively;ii) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1; iii) a VH comprising SEQ ID NO: 1; oriv) SEQ ID NO: 1 and any one of SEQ ID NOs: 41-43 (e.g., SEQ ID NO: 43) optionally without the C-terminal lysine;and the light chain of the anti-IL21R antibody comprises:i) light chain complementarity determining regions (LCDR) 1-3 comprising SEQ ID NOs: 6-8, respectively;ii) a VL comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2;iii) a VL comprising SEQ ID NO: 2; oriv) SEQ ID NOs: 2 and 44.

[0009] The present disclosure also provides an anti-IL21R antibody or an antigen-binding portion thereof, wherein the antibody comprises HCDR1-3 and LCDR1-3 amino acid sequences of:a) SEQ ID NOs: 3-8, respectively;b) SEQ ID NOs: 13-18, respectively;c) SEQ ID NOs: 23-28, respectively;d) SEQ ID NOs: 33-38, respectively;e) SEQ ID NOs: 92-95, 114 and 8, respectively;f) SEQ ID NOs: 98-99, 5, 100, 115 and 8, respectively;g) SEQ ID NOs: 3, 93, 5, 103, 116 and 8, respectively;h) SEQ ID NOs: 106, 93, 5, 111, 114, and 8, respectively;i) SEQ ID NOs: 110, 93, 5, 111, 114, and 8, respectively; orj) SEQ ID NOs: 3, 93, 5, 6-8, respectively.

[0010] In some embodiments, the anti-IL21R antibody comprises a VH amino acid sequence and a VL amino acid sequence that are at least 90% identical to the amino acid sequences of:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively,e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

[0011] In some embodiments, the anti-IL21R antibody comprises a VH and a VL comprising:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively,e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

[0012] In some embodiments, an anti-IL21R antibody herein is of isotype subtype IgGi. In certain embodiments, the antibody comprises a mutant Fc domain with reduced binding affinity for an Fc gamma receptor. The mutant Fc domain may have, for example, a) mutations L234A and L235A, orb) mutations L234A, L235E, and G237A,wherein the mutation positions are numbered according to Eu numbering.In certain embodiments, the antibody comprises a heavy chain constant region comprising SEQ ID NO: 42 or 43 optionally without the C-terminal lysine.

[0013] The present disclosure also provides an anti-IL21R antibody that comprises: a) a heavy chain (HC) comprising SEQ ID NO: 62 optionally without the C-terminal lysine, and a light chain (LC) comprising SEQ ID NO: 63;b) an HC comprising SEQ ID NO: 64 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 65;c) an HC comprising SEQ ID NO: 66 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 67;d) an HC comprising SEQ ID NO: 68 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 69;e) an HC comprising SEQ ID NO: 117 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 118;f) an HC comprising SEQ ID NO: 119 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 120;g) an HC comprising SEQ ID NO: 121 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 122; orh) an HC comprising SEQ ID NO: 123 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 124;i) an HC comprising SEQ ID NO: 125 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 126; orj) an HC comprising SEQ ID NO: 127 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 128

[0014] The present disclosure also provides a multispecific (e.g., bispecific) binding molecule (e.g., antibody) comprising a binding portion of an anti-IL21R antibody or antigenbinding portion herein and a binding portion of another, distinct antibody.

[0015] The present disclosure also provides a pharmaceutical composition comprising an anti-IL21R antibody or antigen-binding portion herein or a bispecific binding molecule herein and a pharmaceutically acceptable excipient.

[0016] The present disclosure also provides isolated nucleic acid molecule(s) comprising a nucleotide sequence that encodes the heavy chain sequence, and a nucleotide sequence that encodes the light chain sequence, of an anti-IL21R antibody or antigen-binding portion herein. In some embodiments, the nucleic acid molecule(s) comprise any one of SEQ ID NOs: 9, 10, 19, 20, 29, 30, 39, 40, 70, 71, 72, 73, 74, 75, 76, 77, 78, 84, 79, 85, 80, 86, 81, 87, 82, 88, 83 and 89. Also provided are vector(s) comprising isolated nucleic acid molecule(s) herein. In some embodiments, the vector(s) further comprise expression control sequence(s).

[0017] The present disclosure also provides a host cell comprising a nucleotide sequence that encodes the heavy chain sequence, and a nucleotide sequence that encodes the light chain sequence, of an anti-IL21R antibody or antigen-binding portion herein. Also provided is a method for producing an anti-IL21R antibody or an antigen-binding portion thereof, comprising- providing such a host cell,- culturing said host cell under conditions suitable for expression of the antibody or antigenbinding portion, and- isolating the resulting antibody or antigen-binding portion.

[0018] The present disclosure also provides a method of treating an autoimmune or inflammatory condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an anti-IL21R antibody or antigen-binding portion herein, a bispecific binding molecule herein, or a pharmaceutical composition herein. Also provided is an anti-IL21R antibody or antigen-binding portion herein, bispecific binding molecule herein, or pharmaceutical composition herein for use in treating an autoimmune or inflammatory condition in a patient in need thereof; and use of an anti-IL21R antibody or antigen-binding portion herein, bispecific binding molecule herein, or pharmaceutical composition herein in the manufacture of a medicament for treating an autoimmune or inflammatory condition in a patient in need thereof. In certain embodiments, the patient is a mammal. In particular embodiments, the patient is a human patient.

[0019] In some embodiments, the condition for treatment is selected from the group consisting of graft-versus-host disease (GvHD), asthma, allergic asthma, chronic spontaneous urticaria (CSU), diabetes (optionally type 1 diabetes or latent autoimmune diabetes), lupus (optionally systemic lupus erythematosus or lupus nephritis), arthritis (optionally rheumatoid arthritis or juvenile arthritis), giant cell arteritis, allergy, antibody -mediated rejection, organ graft rejection, transplant desensitization, Addison’s disease, ankylosing spondylitis, anti-glomerular basement membrane disease, IgA nephropathy, autoimmune hepatitis, primary biliary cholangitis (PBC), celiac disease, autoimmune alopecia, atopic dermatitis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, granulomatosis with polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, autoimmune thyroid disease (AITD), antiphospholipid syndrome, hemolytic anemia, Henoch-Schonlein purpura, juvenile myositis, Kawasaki disease, inflammatory bowel disease (optionally Crohn’s disease or ulcerative colitis), multiple sclerosis, myasthenia gravis, neuromyelitis optica, psoriasis, psoriatic arthritis, Sjogren’s syndrome, systemic scleroderma, systemic sclerosis, immune thrombocytopenia (ITP), thrombocytopenic purpura, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, uveitis, autoimmune uveitis, thyroid eye disease, vasculitis, vitiligo, neuromyelitis optica spectrum disorder (NMOSD), encephalitis, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), and Vogt-Koyanagi -Harada Disease.

[0020] In certain embodiments, the condition is GvHD.

[0021] In certain embodiments, the condition is pemphigus vulgaris, autoimmune hepatitis, vitiligo, antibody-mediated rejection, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

[0022] The present disclosure also provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an anti-IL21R antibody or antigen-binding portion herein, a bispecific binding molecule herein, or a pharmaceutical composition herein. Also provided is an anti-IL21R antibody or antigenbinding portion herein, bispecific binding molecule herein, or pharmaceutical composition herein for use in treating cancer in a patient in need thereof; and use of an anti-IL21R antibody or antigen-binding portion herein, bispecific binding molecule herein, or pharmaceutical composition herein in the manufacture of a medicament for treating cancer in a patient in need thereof. In certain embodiments, the patient is a mammal. In particular embodiments, the patient is a human patient.

[0023] The cancer may be in one or more tissues such as skin, lung, intestine, colon, ovary, brain, prostate, kidney, soft tissues, the hematopoietic system, head and neck, liver, bone, bladder, breast, stomach, uterus, cervix, and pancreas. In a preferred embodiment, the cancer may be multiple myeloma or diffuse large B cell lymphoma (DLBCL).

[0024] Other features, objectives, and advantages of the invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating embodiments and aspects of the invention, is given by way of illustration only, not limitation. Various changes and modification within the scope of the invention will become apparent to those skilled in the art from the detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 is a set of line graphs showing binding of the recited antibodies and isotype control to CHO-S cells transfected with human, cynomolgus, or mouse IL21R or mock-transfected. Data are presented as triplicate means ± SD. A) Antibodies 33628, 33730, 32302, 33726, ATR-107 analogue and Isotype control. B) Affinity-matured variants of antibody 33628 (33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, 33628.40927), ATR-107 analogue and Isotype control.

[0026] FIG. 2 is a pair of line graphs showing the ligand blocking curves of the recited antibodies and isotype control to CHO-S cells transfected with human or cynomolgus IL21R. Data are presented as triplicate means ± SD. A) Antibodies 33628, 33730, 32302, 33726, ATR-107 analogue and Isotype control. B) Affinity-matured variants of antibody 33628(33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, 33628.40927), ATR-107 analogue and Isotype control.

[0027] FIG. 3 is a line graph showing antibody dose-response titration results for a KMS1 l-STAT3-luciferase reporter assay. The assay examines blockade of IL21-IL21R-STAT3 signaling of IL21R-expressing KMS11 target cells as measured by luminescence upon treatment with a recited antibody in the presence of 1 ng / mL IL21. Background signal (no IL21) was deducted, and values normalized to 1 ng / mL IL21 level, as indicated by horizontal dotted lines; error bars represent SEM of triplicate measurements. A) Titration of 33628, 33730, 32302, 33726 versus BOS161721 and Isotype control B) Titration of 33628 versus affinity-matured variants (33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, 33628.40927) as well as the ATR-107 analogue.

[0028] FIG. 4 is a line graph depicting results for a KMS1 l-STAT3-luciferase reporter assay with IL21 titration. The assay examines blockade of IL21-IL21R-STAT3 signaling of IL21R-expressing KMS11 target cells as measured by luminescence upon treatment with a recited antibody in the presence of IL21 at indicated concentrations. Values were normalized to no ligand level; error bars represent SEM of triplicate measurements.

[0029] FIG. 5 is a line graph showing antibody dose-response titration results for a B cell viability assay. The assay examines blockade of IL21-IL21R signaling of IL21R expressing primary B cells as measured by viability (CellTiter-Glo® luminescence signal) upon treatment with a recited antibody in the presence of 50 ng / mL IL21. Values were normalized to the 50 ng / mL IL21 signal level; the background signal and IgGi.3f isotype signal are indicated by horizontal dotted lines. Error bars represent SEM of triplicate measurements.

[0030] FIG. 6 is a line graph showing results for a B cell viability assay with IL21 titration. The assay examines blockade of IL21-IL21R signaling of IL21R expressing primary B cells as measured by viability (CellTiter-Glo® luminescence signal) upon treatment with a recited antibody in the presence of IL21 at indicated concentrations. The X-axis is in log2 scale. Values were normalized to no ligand level; error bars represent SEM of triplicate measurements.

[0031] FIG. 7 is a set of bar graphs showing the ability of the recited antibodies to inhibit IL21-induced p-STATl, p-STAT3, and p-STAT5 signaling in primary B cells from two donors. p-STAT values were normalized to pan-actin. p-STAT5 results were not quantifiable in Donor 2. (A) 33628 and ATR-107 analogue, donor 1; (B) 33628 and ATR-107 analogue, donor 2; (C) 33628.39218, and ATR-107 analogue, donors 1 and 2.

[0032] FIG. 8 is a set of graphs showing the ability of antibody 33628 and 33628.39218 to inhibit differentiation of B cells in PBMCs from healthy donors. Panel A shows inhibition of differentiation of IgG- and IgA- secreting plasma cells upon treatment with 25 pg / mL of 33628, 33628.39218, or ATR-107 analogue. Panel B shows differentiation of IgE-secreting plasma cells upon treatment with a 5-fold titration of 33628.

[0033] FIG. 9 is a line graph showing the effect of the recited antibodies on iTreg differentiation in the presence of IL21. Data represent the mean with standard deviation of the percentage of CD25+FoxP3+cells normalized to the condition without IL21 (100%) and the condition with IL21 (0%) from six donors.

[0034] FIG. 10 is a line graph showing specific lysis of the IL21R expressing RAJI target cell line as measured by calcein release upon treatment with the recited antibodies or a wildtype IgGi control antibody (IgGiwt) in the presence of healthy donor PBMCs. Results are also shown for positive control antibodies 32355 and ATR107 analogue in the IgGiwt format. Spontaneous lysis (no PBMCs present) was deducted, and values normalized to maximal lysis. The horizontal dotted line represents untreated signal level; error bars represent SEM of triplicate measurements.

[0035] FIG. 11 is a pair of bar graphs showing DNA and insulin ELISA assay results that depict the polyreactivity of the recited antibodies.

[0036] FIG. 12 is a set of graphs showing the effect of antibody 33628 treatment in vivo on inhibition of GvHD in immunodeficient NRG mice injected with human PBMCs. Body weight, GvHD score, and mortality were assessed. Mice treated with 33628 increased in weight (Panel A), presented with fewer signs of disease (Panel B), and had lower mortality (Panel C, Kaplan-Meier analysis), as compared to vehicle-treated animals. Data are shown as mean ± SEM.

[0037] FIG. 13 is a set of graphs showing the effect of antibody 33628 treatment on the presence of human cells in dissected spleens of immunodeficient NRG mice injected with human PBMCs, assessed by flow cytometric analysis. Panel A shows detection of human engraftment by the pan-hematopoietic CD45 marker. Panels B-D show the frequency of CD4+T cells, CD25+FoxP3+regulatory T cells, and CD8+cytotoxic T cells, respectively.

[0038] FIG. 14 A and B is a line graph showing results of an in vivo single dose pharmacokinetic (PK) study of the recited antibodies in hFcRn mice.

[0039] FIG. 15 represents the structure of the IL21R extracellular domain bound to Fab 33628. Panel A is a cartoon representation of IL21R-ECD bound to Fab 33628. IL21R is shown in dark grey. The Fab 33628 heavy chain is shown in grey, and the Fab 33628 lightchain is shown in light grey. The anti-Fab VHH (VHH-Nb) is shown in mouse-grey. Fab 33628 interacts predominantly with the N-terminal domain 1 of IL21R. Panel B shows the local resolution map colored by a grey color gradient with areas with a local resolution of 2.5 A shown in dark grey, areas with a local resolution of 3 A shown in white, and areas with a local resolution of 5+ A shown in light grey. The resolution of IL21R is on average lower than the resolution of Fab 33628. The resolution of IL21R is highest closer to the epitope region.

[0040] FIG. 16 represents the epitope binding region of the IL21R extracellular domain bound to Fab 33628. IL21R is shown in dark grey. The Fab 33628 heavy chain is shown in grey and the Fab 33628 light chain is shown in light grey. The image on the left is rotated 180 degrees compared to the image on the right. Key interactions include R91L and R93L of the LCDR3 of Fab 33628 forming salt bridges with IL21R, R58H of the HCDR1 hydrogen bonding with Y36 and H68, and Q27L of the LCDR1 hydrogen bonding with S92.

[0041] FIG. 17 represents the epitope binding region of the IL21R extracellular domain bound to Fab 33628. IL21R is shown in dark grey and the top-down view of Fab 33628 is shown as a surface representation. Panel A: The Fab 33628 heavy chain is shown in grey, and the Fab 33628 light chain is shown in light grey. Panel B: Fab 33628 colored by surface electrostatics. A positive charged patch on Fab 33628 is responsible for interactions with negatively charged residues on IL21R. There are also some small negatively charged areas on Fab 33628.

[0042] FIG. 18 is a schematic showing the design of the experiment in Example 15. Keyhole limpet hemocyanin (KLH) is administered at the timepoints shown, with subcutaneous injection of 33628 antibody, ATR-107 and vehicle at the timepoints shown.

[0043] FIG. 19 is a scatter dot plot showing quantification of anti-KLH IgG by ELISA in mouse plasma from the KLH model. The group receiving vehicle is represented by white circles, the group receiving antibody 33628 is represented by light grey circles, the group receiving the ATR-107 analogue is represented by dark grey circles, and the group receiving cyclosporin A is represented by black circles. Data are expressed as mean + / - SD.DETAILED DESCRIPTION OF THE INVENTION

[0044] The present disclosure provides new antibodies that specifically bind to IL21R (“anti-IL21R antibodies”), or antigen-binding portions thereof. In some embodiments, the antibodies or antigen-binding portions are antagonistic, and can be used to block the interaction of IL21R with its ligand IL21. The present antibodies can modulate the immunesystem in a patient and may be used for treatment of autoimmune disorders or inflammatory disorders.

[0045] Unless otherwise stated, “IL21R” refers to human IL21R. A human IL21R polypeptide sequence is available under UniProt Accession No. Q9HBE5, as shown below (signal peptide underlined):MPRGWAAPLLLLLLQGGWGCPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELK DEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESI KPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLIS VDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGWNP HLLLLLLLVIVFIPAFWSLKTHPLWRLWKKIWAVPSPERFFMPLYKGCSGDFKKWVGAP FTGSSLELGPWSPEVPSTLEVYSCHPPRSPAKRLQLTELQEPAELVESDGVPKPSFWPT AQNSGGSAYSEERDRPYGLVSIDTVTVLDAEGPCTWPCSCEDDGYPALDLDAGLEPSPG LEDPLLDAGTTVLSCGCVSAGSPGLGGPLGSLLDRLKPPLADGEDWAGGLPWGGRSPGG VSESEAGSPLAGLDMDTFDSGFVGSDCSSPVECDFTSPGDEGPPRSYLRQWVVIPPPLS SPGPQAS ( SEQ ID NO : 57 )A cynomolgus monkey IL21R polypeptide sequence is available under GenBank Accession No. XP_005591578, as shown below (signal peptide underlined):MLRGWAAPLLLLLLQGGWGCPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELK DEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNVTDHSGNYTQECGSFLLADSI KPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLIS VDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGWNP HLLLLLLLVIVFIPAFWSLKTHPMWRLWKKIWAVPSPEQFFVPLYKGCSGDFKKWVGAP FTGSRLELGPWSPEVPSALEVYSCHPPQSPAKRLQLTELQEPTELVESDGVSKPSFWAT AQNSGGSAYSEERDRPYGVVSIDTVTVLDAEGPCTWPCSCEDDGYPALDLDAGLEPSPG LEDPLLGAGTTVLSCGCVSAGSPGLGGPLGSLLDRLKPPLADGEDWAGGLPWGGRSPGG VSESEAGSPPAGLDMDTFDSGFVGSDCSSPVECDFTTPGDEGPPRSYLRQWVVIPPPLS SPGPQAS ( SEQ ID NO : 58 )A mouse IL21R polypeptide sequence is available under UniProt Accession No. Q9JHX3, as shown below (signal peptide underlined):MPRGPVAALLLLILHGAWSCLDLTCYTDYLWTITCVLETRSPNPSILSLTWQDEYEELQ DQETFCSLHRSGHNTTHIWYTCHMRLSQFLSDEVFIVNVTDQSGNNSQECGSFVLAESI KPAPPLNVTVAFSGRYDISWDSAYDEPSNYVLRGKLQYELQYRNLRDPYAVRPVTKLIS VDSRNVSLLPEEFHKDSSYQLQVRAAPQPGTSFRGTWSEWSDPVIFQTQAGEPEAGWDP HMLLLLAVLIIVLVFMGLKIHLPWRLWKKIWAPVPTPESFFQPLYREHSGNFKKWVNTP FTASSIELVPQSSTTTSALHLSLYPAKEKKFPGLPGLEEQLECDGMSEPGHWCIIPLAA GQAVSAYSEERDRPYGLVSIDTVTVGDAEGLCVWPCSCEDDGYPAMNLDAGRESGPNSE DLLLVTDPAFLSCGCVSGSGLRLGGSPGSLLDRLRLSFAKEGDWTADPTWRTGSPGGGS ESEAGSPPGLDMDTFDSGFAGSDCGSPVETDEGPPRSYLRQWVVRTPPPVDSGAQSS( SEQ ID NO : 59)

[0046] The term “antibody” (Ab) or “immunoglobulin” (Ig), as used herein, refers to a tetramer comprising two heavy chains (HCs) (about 50-70 kDa) and two light chains (LCs) (about 25 kDa) inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant region (CH). Each light chainis composed of a light chain variable domain (VL) and a light chain constant region (CL). The VH and VL domains can be subdivided further into regions of hypervariability, termed “complementarity determining regions” (CDRs), interspersed with regions that are more conserved, termed “framework regions” (FRs). Each VH and VL is composed of three CDRs (H-CDR herein designates a CDR from the heavy chain; and L-CDR herein designates a CDR from the light chain) and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The assignment of amino acid numbers, and of FR and CDR regions, in the heavy or light chain may be in accordance with IMGT® definitions (Lefranc et al., Dev Comp Immunol. (2003) 27(1):55-77); or the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J Mol Biol. (1987) 196:901-17; Chothia et al., Nature (1989) 342:878-83; MacCallum et al., J Mol Biol. (1996) 262:732-45; or Honegger and Pliickthun, J Mol Biol. (2001) 309(3):657-70.

[0047] The term “recombinant antibody” refers to a non-naturally occurring antibody that is expressed from a cell or cell line comprising the nucleotide sequence(s) that encode the antibody, wherein said nucleotide sequence(s) are not naturally associated with the cell.

[0048] The term “isolated protein,” “isolated polypeptide” or “isolated antibody” refers to a protein, polypeptide or antibody that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, and / or (4) does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components. A protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art. Such naturally associated components may include, e.g., nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, cellular debris, growth medium, etc.

[0049] The term “affinity” refers to a measure of the attraction between an antigen and an antibody. The intrinsic attractiveness of the antibody for the antigen is typically expressed as the binding affinity equilibrium constant (KD) of a particular antibody-antigen interaction. An antibody is said to specifically bind to an antigen when the KD for the binding is < 1 pM, e.g., < 100 nM or < 10 nM. A KD binding affinity constant can be measured, e.g., by surface plasmon resonance (Biacore™) using the Biacore™ T200 system, the IBIS MX96 SPR system from IBIS Technologies, or the Carterra LSA SPR platform, or by bio-layerinterferometry, for example using the Octet™ system from ForteBio.

[0050] The term “epitope” as used herein refers to a portion (determinant) of an antigen that is bound by an antigen-binding protein (e.g., an antibody or an antigen -binding portion thereof). For example, an epitope may refer to the portion of an antigen that specifically binds to an antigen-binding site of an antigen-binding protein (e.g., an antibody or antigenbinding portion thereof), wherein the antigen-binding site is known as a paratope. Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and generally have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antigen may have more than one epitope.

[0051] An epitope may be “linear” or “conformational.” In a linear epitope, all of the points of interaction between a protein (e.g., an antigen) and an interacting molecule (e.g., an antibody) occur linearly along the primary amino acid sequence of the protein. In a conformational epitope, the points of interaction occur across amino acid residues on the protein that are separated from one another in the primary amino acid sequence. A “functional” epitope refers to residues that directly contribute to the affinity of the antigen / antigen-binding protein interaction. Epitopes may be determined using methods such as, e.g., alanine scanning mutational analysis, peptide blot analysis, peptide cleavage analysis, crystallographic studies, NMR analysis, and hydrogen / deuterium exchange detected by mass spectrometry.

[0052] Once a desired epitope on an antigen is determined, it is possible to generate antibodies to that epitope using techniques well known in the art. For example, an antibody to a linear epitope may be generated, e.g., by immunizing an animal with a peptide having the amino acid residues of the linear epitope. An antibody to a conformational epitope may be generated, e.g., by immunizing an animal with a mini -domain containing the relevant amino acid residues of the conformational epitope. An antibody to a particular epitope can also be generated, e.g., by immunizing an animal with the target molecule of interest (e.g., IL21R) or a relevant portion thereof, then screening for binding to the epitope. An antibody to a particular epitope also may be generated using phage display methods.

[0053] One can determine whether an antibody binds to the same epitope as or competes for binding to IL21R with an anti-IL21R antibody of the present disclosure by using methods known in the art, including, without limitation, competition assays, epitope binning, and alanine scanning. In some embodiments, one allows the antibody of the present disclosure to bind to the antigen under saturating conditions, and then measures the ability of the testantibody to bind to that antigen. If the test antibody is able to bind to the antigen at the same time as the reference antibody, then the test antibody binds to a different epitope than the reference antibody. However, if the test antibody is not able to bind to the antigen at the same time, then the test antibody binds to the same epitope, an overlapping epitope, or an epitope that is in close proximity to the epitope bound by the antibody of the present disclosure. To test whether an antibody cross-competes with another antibody, one may use the competition method described above in two directions, i.e., determining if the known antibody blocks the test antibody and vice-versa. Competition or cross-competition experiments can be performed using, e.g., ELISA, RIA, Biacore™, SPR, Bio-Layer Interferometry or flow cytometry. For example, the experiments may be performed, e.g., using a Biacore™ T200, IBIS MX96, or Carterra LSA SPR instrument or the Octet™ system.

[0054] One can also determine whether an antibody binds to an epitope, e.g. a conformational epitope, of IL21Rby cryo-electron microscopy (cryo-EM) of a complex of e.g. the extracellular domain (ECD) of IL21R with the antibody, or an antigen-binding fragment thereof such as a Fab. 2D data collected from the cryo-EM of the complex are processed to generate a 3D density map which is used for modeling the interaction of IL21R ECD with the antibody and identify the residues of the antibody and the IL21R ECD involved in binding interactions. Reference is made to herein example 14 for further details.

[0055] The term “polyreactive” or “polyreactivity” denotes the unintended binding of an antibody to either off-target / unrelated biomolecules, or formulation excipients. A classic method of evaluating polyreactivity of antibodies is ELISA (Enzyme-Linked Immunosorbent Assay) (Carnero et al., 2025, Journal of Immunological Methods, Vol. 539, 113855), e.g. DNA and / or insulin ELISA assay.

[0056] The term “human antibody” refers to an antibody in which the variable domains and constant region sequences are derived from human sequences. The term encompasses antibodies with sequences that are derived from human genes but have been modified, e.g., to decrease immunogenicity, increase affinity, and / or increase stability. Further, the term encompasses antibodies produced recombinantly in nonhuman cells, which may impart glycosylation not typical of human cells. The term also encompasses antibodies produced in transgenic nonhuman organisms with human antibody genes (e.g., OmniRat® rats).

[0057] The term “antigen-binding portion” or “antigen-binding fragment” of an antibody, or simply “antibody portion,” as used herein, refers to one or more portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human IL21R, or portion(s) thereof). It has been shown that certain fragments of a full-length antibody canperform the antigen-binding function of the antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” include (i) a Fab fragment: a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab’)2 fragment: a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CHI domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment, which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) capable of specifically binding to an antigen (e.g., a CDR3 peptide or a FR3-CDR3-FR4 peptide). Further, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH domains pair to form a monovalent molecule (known as single chain Fv (scFv)). Also within the present disclosure are antigen-binding molecules comprising a VH and / or a VL. In the case of a VH, the molecule may also comprise one or more of a CHI, hinge, CH2, or CH3 region. Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites. Also contemplated are tribodies, tetrabodies, nanobodies (e.g., monovalent or bivalent nanobodies), minibodies, domain-specific antibodies, single domain antibodies, and domain-deleted antibodies.

[0058] Antigen-binding portions, such as Fab and F(ab’)2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion of whole antibodies. Moreover, antibodies, antigen-binding portions and immunoadhesin molecules can be obtained using standard recombinant DNA techniques, e.g., as described herein.

[0059] The class (isotype) and subclass of anti-IL21R antibodies described herein may be determined by any method known in the art. In general, the class and subclass of an antibody may be determined using antibodies that are specific for a particular class and subclass of antibody. Such antibodies are available commercially. The class and subclass can be determined by ELISA or Western blot as well as other techniques. Alternatively, the class and subclass may be determined by sequencing all or a portion of the constant regions of theheavy and / or light chains of the antibodies, comparing their amino acid sequences to the known amino acid sequences of various classes and subclasses of immunoglobulins, and determining the class and subclass of the antibodies.

[0060] Unless otherwise indicated, the numbering of all antibody amino acid residues in this disclosure is according to the IMGT® numbering scheme.I. Anti-IL21R Antibodies and Binding Proteins

[0061] The present disclosure provides anti-IL21R antibodies and antigen-binding portions thereof, as well as binding proteins comprising said antibodies or antigen-binding portions. In a certain aspect, the antibodies disclosed herein are human antibodies generated from transgenic animals (e.g., rats) that are able to produce antibodies encoded by rearranged human antibody genes. In particular embodiments, the human antibodies may contain certain mutations, e.g., to change primer-derived mutations back to the germline sequence.

[0062] In some embodiments, the anti-IL21R antibody or antigen-binding portion competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody comprising HC and LC sequences that comprise:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively;e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

[0063] The assignment of CDR regions for the anti-IL21R antibodies herein may be in accordance with any method known in the art, such as IMGT®, Kabat, Chothia, Martin, Contact, or AHo definitions, or any combination of any of these definitions (Kabat plus Chothia, for example). For instance, references herein to HCDR1-3 and LCDR1-3 of an antibody of the present invention by one definition (such as IMGT®) may be replaced by references to HCDR1-3 and LCDR1-3 of that antibody as indicated by any of the other definitions herein. Also contemplated are sets of CDRs wherein each of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 may individually be specified according to any of themethods for defining CDRs herein (e.g., HCDR1 specified by the Kabat definition, HCDR2 specified by the Chothia definition, etc.).

[0064] In some embodiments, the anti-IL21R antibody or antigen-binding portion has HCDR1-3 comprising SEQ ID NOs: 3-5; 13-15; 23-25; 33-35; 92-94; 98-99 and 5; 3, 93, and 5; 106, 93 and 5; 110, 93 and 5; or 3, 93 and 5, respectively.

[0065] In some embodiments, the anti-IL21R antibody or antigen-binding portion has a VH amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, 11, 21, 31, 90, 96, 101, 104, 108, or 112. In certain embodiments, any variations from the selected sequence are in the framework regions (FRs).

[0066] In some embodiments, the anti-IL21R antibody or antigen-binding portion has a VHcomprising SEQ ID NO: 1, 11, 21, 31, 90, 96, 101, 104, 108, or 112.

[0067] In some embodiments, the anti-IL21R antibody has a VH amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, 11, 21, 31, 90, 96, 101, 104, 108, or 112(optionally wherein any variations from the selected sequence are in the FRs); and a heavy chain constant region amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 41-43 (optionally without the C-terminal lysine).

[0068] In some embodiments, the anti-IL21R antibody comprises a VH amino acid sequence of SEQ ID NO: 1, 11, 21, 31, 90, 96, 101, 104, 108, or 112, and a heavy chain constant region amino acid sequence of any one of SEQ ID NOs: 41-43 (e.g., SEQ ID NO: 43) optionally without the C-terminal lysine.

[0069] In some embodiments, the anti-IL21R antibody comprises an HC amino acid sequence of SEQ ID NO: 62, 64, 66, 68, 117, 119, 121, 123, 125 or 127, optionally without the C-terminal lysine.

[0070] In some embodiments, the anti-IL21R antibody or antigen-binding portion has LCDR1-3 comprising SEQ ID NOs: 6-8; 16-18; 26-28; 36-38; 95, 114, and 8; 100, 115 and 8; 103, 116 and 8; 107, 116 and 8; or 111, 114 and 8, respectively.

[0071] In some embodiments, the anti-IL21R antibody or antigen-binding portion has a VL amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, 12, 22, 32, 91, 97, 102, 105, 109, or 113. In certain embodiments, any variations from the selected sequence are in the FRs.

[0072] In some embodiments, the anti-IL21R antibody or antigen-binding portion has a VLcomprising SEQ ID NO: 2, 12, 22, 32, 91, 97, 102, 105, 109, or 113.

[0073] In some embodiments, the anti-IL21R antibody has a VL amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, 12, 22, 32, 91, 97, 102, 105, 109, or 113 (optionally wherein any variations from the selected sequence are in the FRs); and a light chain constant region amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 44.

[0074] In some embodiments, the anti-IL21R antibody comprises a VL amino acid sequence of SEQ ID NO: 2, 12, 22, 32, 91, 97, 102, 105, 109, or 113 and a light chain constant region amino acid sequence of SEQ ID NO: 44.

[0075] In some embodiments, the anti-IL21R antibody comprises an LC amino acid sequence of SEQ ID NO: 63, 65, 67, 69, 118, 120, 122, 124, 126, or 128.

[0076] In certain embodiments, the anti-IL21R antibody or antigen-binding portion comprises any one of the above-described heavy chain sequences and any one of the abovedescribed light chain sequences.

[0077] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises the HCDR1-3 and LCDR1-3 amino acid sequences of:a) SEQ ID NOs: 3-8, respectively;b) SEQ ID NOs: 13-18, respectively;c) SEQ ID NOs: 23-28, respectively;d) SEQ ID NOs: 33-38, respectively;e) SEQ ID NOs: 92-95, 114 and 8, respectively;f) SEQ ID NOs: 98-99, 5, 100, 115 and 8, respectively;g) SEQ ID NOs: 3, 93, 5, 103, 116 and 8, respectively;h) SEQ ID NOs: 106, 93, 5, 107, 116, and 8, respectively;i) SEQ ID NOs: 110, 93, 5, 111, 114, and 8, respectively; orj) SEQ ID NOs: 3, 93, 5, 6-8, respectively.

[0078] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) to:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively;e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.In certain embodiments, any variations from the selected sequences are in the FRs.

[0079] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that comprise:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively;e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

[0080] In some embodiments, the anti-IL21R antibodies of the present disclosure have the “LALA” mutations (L234A / L235A) in the Fc region. These mutations hinder binding of the antibodies to human FcyR (Fc gamma receptors). Additionally, or alternatively, the anti-IL21R antibodies may have a G237A mutation in the Fc region. “IgGi-3f ’ refers to the presence of the L234A, L235E, and G237A mutations, which are known to reduce effector function of the Fc region of IgGi antibodies (WO 88 / 07089). All Fc region positions are defined according to Eu numbering unless otherwise stated.

[0081] In some embodiments, the anti-IL21R antibody of the present disclosure comprises:a) an HC comprising SEQ ID NOs: 1 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 2 and 44;b) an HC comprising SEQ ID NOs: 11 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 12 and 44;c) an HC comprising SEQ ID NOs: 21 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 22 and 44;d) an HC comprising SEQ ID NOs: 31 and 43 (optionally without the C-terminallysine) and an LC comprising SEQ ID NOs: 32 and 44;e) an HC comprising SEQ ID NOs: 90 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 91 and 44;f) an HC comprising SEQ ID NOs: 96 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 97 and 44;g) an HC comprising SEQ ID NOs: 101 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 102 and 44;h) an HC comprising SEQ ID NOs: 104 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 105 and 44;i) an HC comprising SEQ ID NOs: 108 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 109 and 44; orj) an HC comprising SEQ ID NOs: 112 and 43 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 113 and 44.

[0082] In some embodiments, the anti-IL21R antibody of the present disclosure comprises:a) an HC comprising SEQ ID NOs: 1 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 2 and 44;b) an HC comprising SEQ ID NOs: 11 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 12 and 44;c) an HC comprising SEQ ID NOs: 21 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 22 and 44;d) an HC comprising SEQ ID NOs: 31 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 32 and 44;e) an HC comprising SEQ ID NOs: 90 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 91 and 44;f) an HC comprising SEQ ID NOs: 96 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 97 and 44;g) an HC comprising SEQ ID NOs: 101 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 102 and 44;h) an HC comprising SEQ ID NOs: 104 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 105 and 44;i) an HC comprising SEQ ID NOs: 108 and 42 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 109 and 44; orj) an HC comprising SEQ ID NOs: 112 and 42 (optionally without the C-terminallysine) and an LC comprising SEQ ID NOs: 113 and 44.

[0083] In some embodiments, the anti-IL21R antibody of the present disclosure comprises:a) an HC comprising SEQ ID NOs: 1 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 2 and 44;b) an HC comprising SEQ ID NOs: 11 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 12 and 44;c) an HC comprising SEQ ID NOs: 21 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 22 and 44;d) an HC comprising SEQ ID NOs: 31 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 32 and 44;e) an HC comprising SEQ ID NOs: 90 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 91 and 44;f) an HC comprising SEQ ID NOs: 96 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 97 and 44;g) an HC comprising SEQ ID NOs: 101 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 102 and 44;h) an HC comprising SEQ ID NOs: 104 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 105 and 44;i) an HC comprising SEQ ID NOs: 108 and 41 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 109 and 44; orj) an HC comprising SEQ ID NOs: 112 and 413 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NOs: 113 and 44.

[0084] In some embodiments, the anti-IL21R antibody of the present disclosure comprises:a) an HC comprising SEQ ID NO: 62 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 63;b) an HC comprising SEQ ID NO: 64 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 65;c) an HC comprising SEQ ID NO: 66 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 67;d) an HC comprising SEQ ID NO: 68 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 69;e) an HC comprising SEQ ID NO: 117 (optionally without the C-terminal lysine)and an LC comprising SEQ ID NO: 118;f) an HC comprising SEQ ID NO: 119 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 120;g) an HC comprising SEQ ID NO: 121 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 122; orh) an HC comprising SEQ ID NO: 123 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 124;i) an HC comprising SEQ ID NO: 125 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 126; orj) an HC comprising SEQ ID NO: 127 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 128.

[0085] The present disclosure also provides an anti-IL21R antibody or an antigen-binding portion thereof that competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927. In some embodiments, the anti-IL21R antibody or an antigen-binding portion thereof that competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, an antibody comprising the VH and VL of antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927, as disclosed in Table 2 and Table 9.

[0086] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927. In some embodiments, the anti-IL21R antibody or antigenbinding portion of the present disclosure comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 33628, 33628.39191, 33628.39218, or 33628.39219.

[0087] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927. In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of antibody 33628,33628.39191, 33628.39218, or 33628.39219. In certain embodiments, any variations from the VH and VL sequences of the selected antibody are in the FRs.

[0088] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are the VH and VL, respectively, of antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927. In some embodiments, the anti-IL21R antibody or antigenbinding portion of the present disclosure comprises a VH and a VL that are the VH and VL, respectively, of antibody 33628, 33628.39191, 33628.39218, or 33628.39219.

[0089] In some embodiments, the anti-IL21R antibody of the present disclosure is antibody 33628, 32302, 33726, 33733, 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927, or an antibody with the same amino acid sequences as said antibody.

[0090] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 1 and an LC that comprises SEQ ID NO: 2;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 4, 6, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 3-8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 1 and 2, respectively (optionally wherein any variations from SEQ ID NOs: 1 and 2 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 1 and 2, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 1 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 2 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 1 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 2 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 1 and 41(optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 2 and 44; or- comprises an HC comprising SEQ ID NO: 62 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 63.

[0091] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 11 and an LC that comprises SEQ ID NO: 12;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 14, 16, and 18, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 13-18, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 11 and 12, respectively (optionally wherein any variations from SEQ ID NOs: 11 and 12 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 11 and 12, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 11 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 12 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 11 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 12 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 11 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 12 and 44; or- comprises an HC comprising SEQ ID NO: 64 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 65.

[0092] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 21 and an LC thatcomprises SEQ ID NO: 22;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 24, 26, and 28, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 23-28, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 21 and 22, respectively (optionally wherein any variations from SEQ ID NOs: 21 and 22 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 21 and 22, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 21 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 22 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 21 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 22 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 21 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 22 and 44; or- comprises an HC comprising SEQ ID NO: 66 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 67.

[0093] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 31 and an LC that comprises SEQ ID NO: 32;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 34, 36, and 38, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 33-38, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 1 and 2, respectively (optionally wherein any variations from SEQ ID NOs: 31and 32 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 31 and 32, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 31 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 32 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 31 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 32 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 31 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 32 and 44; or- comprises an HC comprising SEQ ID NO: 68 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 69.

[0094] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 117, and an LC that comprises SEQ ID NO: 118;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 93, 95, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 92-95, 114 and 8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 90 and 91, respectively (optionally wherein any variations from SEQ ID NOs: 90 and 91 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 90 and 91, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 90 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 91 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 90 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences ofSEQ ID NOs: 91 and 44; or- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 90 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 91 and 44.

[0095] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 119, and an LC that comprises SEQ ID NO: 120;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 99, 100, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 98-99, 5, 100, 115, and 8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 96 and 97, respectively (optionally wherein any variations from SEQ ID NOs: 96 and 97 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 96 and 97, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 96 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 97 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 96 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 97 and 44; or- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 96 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 97 and 44.

[0096] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 121, and an LC that comprises SEQ ID NO: 122;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 93, 103,and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 3, 93, 5, 103, 116, and 8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 101 and 102, respectively (optionally wherein any variations from SEQ ID NOs: 101 and 102 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 101 and 102, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 101 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 102 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 101 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 102 and 44; or- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 101 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 102 and 44.

[0097] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 123, and an LC that comprises SEQ ID NO: 124;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 93, 107, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 106, 93, 5, 107, 116, and 8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 104 and 105, respectively (optionally wherein any variations from SEQ ID NOs: 104 and 105 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 104 and 105, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 104 and 43(optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 105 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 104 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 105 and 44; or- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 104 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 105 and 44.

[0098] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 125, and an LC that comprises SEQ ID NO: 126;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 93, 111, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 110, 93, 5, 111, 114, and 8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 108 and 109, respectively (optionally wherein any variations from SEQ ID NOs: 108 and 109 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 108 and 109, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 108 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 109 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 108 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 109 and 44; or- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 108 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 109 and 44.

[0099] Also contemplated by the present disclosure is an anti-IL21R antibody or an antigen-binding portion thereof, wherein said anti-IL21R antibody- competes or cross-competes for binding to human IL21R with, or binds to the same epitope of human IL21R as, an antibody with an HC that comprises SEQ ID NO: 127, and an LC that comprises SEQ ID NO: 128;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of SEQ ID NOs: 93, 6, and 8, respectively;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 3, 93, 5, and 6-8, respectively;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) in amino acid sequence to SEQ ID NOs: 112 and 113, respectively (optionally wherein any variations from SEQ ID NOs: 112 and 113 are in the FRs);- comprises a VH and a VL that comprise the amino acid sequences of SEQ ID NOs: 112 and 113, respectively;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 112 and 43 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 113 and 44;- comprises an HC comprising the amino acid sequences of SEQ ID NOs: 112 and 42 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 113 and 44; or

[0100] - comprises an HC comprising the amino acid sequences of SEQ ID NOs: 112 and 41 (optionally without the C-terminal lysine) and an LC comprising the amino acid sequences of SEQ ID NOs: 113 and 44. In some embodiments, the anti-IL21R antibody- competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927;- comprises HCDR2, LCDR1, and LCDR3 amino acid sequences of antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218,33628.39219, 33628.39223, 33628.39230, or 33628.40927 (optionally wherein any variations from the VH and VL of the antibody are in the FRs);- comprises a VH and a VL that are the VH and VL, respectively, of antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927; or- is antibody 33628, or an affinity matured variant thereof 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, or 33628.40927, or an antibody with the same amino acid sequences as said antibody.

[0101] In some embodiments, the anti-IL21R antibody- competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, antibody 32302;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 32302;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of antibody 32302 (optionally wherein any variations from the VH and VL of antibody 32302 are in the FRs);- comprises a VH and a VL that are the VH and VL, respectively, of antibody 32302; or - is antibody 32302, or an antibody with the same amino acid sequences as said antibody.

[0102] In some embodiments, the anti-IL21R antibody- competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, antibody 33726;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 33726;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of antibody 33726 (optionally wherein any variations from the VH and VL of antibody 33726 are in the FRs);- comprises a VH and a VL that are the VH and VL, respectively, of antibody 33726; or - is antibody 33726, or an antibody with the same amino acid sequences as said antibody.

[0103] In some embodiments, the anti-IL21R antibody- competes or cross-competes for binding to IL21R with, or binds to the same epitope of IL21R as, antibody 33733;- comprises the HCDR1-3 and LCDR1-3 amino acid sequences of antibody 33733;- comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, ofantibody 33733 (optionally wherein any variations from the VH and VL of antibody 33733 are in the FRs);- comprises a VH and a VL that are the VH and VL, respectively, of antibody 33733; or - is antibody 33733, or an antibody with the same amino acid sequences as said antibody.

[0104] In some embodiments, a “variant” antibody or antigen-binding portion, having amino acid substitutions (which may be conservative or non-conservative) from an antibody or antigen-binding portion exemplified herein, does not have substantially altered biologic activity from the exemplified antibody or antigen-binding portion. For example, the variant antibody or antigen-binding portion may retain at least 50%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding affinity of the parent antibody or antigen -binding portion, or may exceed the binding affinity of the parent antibody or antigen-binding portion. In some embodiments, a variant antibody or an antigen-binding portion thereof may have mutations, e.g., that increase its half-life, alter its immunogenicity, provide a site for covalent or non-covalent binding to another molecule, etc. In certain embodiments, the variant antibody or antigen-binding portion thereof may have mutations in its FRs (e.g., in one, two, three, four, five, six, seven, or eight of its FRs). In certain embodiments, the variant antibody or antigenbinding portion thereof may have mutations in its CDRs (e.g., in one, two, three, four, five, or six of its CDRs). In certain embodiments, the variant antibody or antigen-binding potion thereof may have mutations in its constant regions.

[0105] The class of an anti-IL21R antibody described herein may be changed or switched with another class or subclass. In some embodiments of the present disclosure, a nucleic acid molecule encoding the VL or VH of the antibody is isolated using methods well known in the art such that it does not include nucleic acid sequences encoding CL or CH, respectively. The nucleic acid molecules encoding VL or VH then are operatively linked to a nucleic acid sequence encoding a CL or CH, respectively, from a different class or subclass of immunoglobulin molecule. This may be achieved using a vector or nucleic acid molecule that comprises a CL or CH sequence, as described above. For example, an anti-IL21R antibody that was originally IgM may be class switched to IgG. Further, the class switching may be used to convert one IgG subclass to another, e.g., from IgGi to IgG?. A K light chain constant region can be changed, e.g., to a light chain constant region, or vice-versa.

[0106] The anti-IL21R antibody of the present disclosure can be an IgG, an IgM, an IgE, an IgA, or an IgD molecule, but is typically of the IgG isotype, e.g., of IgG subclass IgGi, IgG?aor IgG?b, IgGs or IgG4. In some embodiments, the antibody is of the isotype subclass IgGi.

[0107] In some embodiments, the anti-IL21R antibody may comprise at least one mutation in the Fc region. A number of different Fc mutations are known, where these mutations alter, e.g., the antibody’s effector functions or half-life. For example, in some embodiments, the anti-IL21R antibody comprises at least one mutation in the Fc region that reduces effector function.

[0108] In some embodiments, the anti-IL21R antibody or antigen-binding portion of the present disclosure is antagonistic.

[0109] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to human IL21R with a KD of 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 nM or less (e.g., 2 nM or less) as measured by surface plasmon resonance (e.g., as described in Example 3).

[0110] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to cynomolgus IL21R with a KD of 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 nM or less (e.g., 3 nM or less) as measured by surface plasmon resonance (e.g., as described in Example 3). In other embodiments, the anti-IL21R antibody or antigen-binding portion does not bind to cynomolgus IL21R, or does not bind with high affinity (e.g., has a KD of >10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM).[OHl] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to human IL21R expressed on CHO-S cells, such as with an ECso of 20, 15, 10, 8, 7, 6, 5, 4, 3, 2, 1, 0.7, or 0.5 nM or less (e.g., 5 nM or less or 1 nM or less) and / or with an efficacy of at least 500000, 600000, 700000, 800000, 900000, or 1000000 (e.g., at least 800000) (e.g., as determined using assays such as those described in Example 4).

[0112] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to cynomolgus IL21R expressed on CHO-S cells, such as with an ECso of 20, 15, 10, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 nM or less (e.g., 6 nM or less or 5 nM or less) and / or with an efficacy of at least 500000, 600000, 700000, 800000, 900000, or 1000000 (e.g., at least 800000) (e.g., as determined using assays such as those described in Example 4).

[0113] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to mouse IL21R expressed on CHO-S cells, such as with an ECso of 30, 20, 15, 13, 10, 9, 7, 5, 4, 3 or 2 nM or less (e.g., 13 nM or less) and / or with an efficacy of at least 50000, 60000, 70000, 80000, 90000, or 100000 (e.g., at least 80000) (e.g., as determined using assays such as those described in Example 4). In other embodiments, the anti-IL21R antibody or antigenbinding portion does not bind to mouse IL21R.

[0114] In some embodiments, the anti-IL21R antibody or antigen-binding portion blocks binding of IL21 to human IL21R which may be transiently expressed on CHO-S cells, suchas with an IC50 of 20, 15, 10, 9, 8, 7, 6, or 5 nM or less (e.g., 7 nM or less) and / or with residual IL21 binding of 20, 18, 16, 15, 14, 13, 12, 11, or 10% or less (e.g., 13% or less) (e.g., as determined using assays such as those described in Example 5).

[0115] In some embodiments, the anti-IL21R antibody or antigen-binding portion blocks binding of IL21 to cynomolgus IL21R which may be transiently expressed on CHO-S cells, such as with an IC50 of 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, 10, 9, 8, 7, 6, or 5 nM or less (e.g., 70 nM or less or 7 nM or less) and / or with residual IL21 binding of 80, 70, 60, 50, 40, 30, 20, 18, 16, 15, 14, 13, 12, 11, or 10% or less (e.g., 60% or less or 13% or less) (e.g., as determined using assays such as those described in Example 5).

[0116] In some embodiments, the anti-IL21R antibody or antigen-binding portion reduces IL21 -induced STAT3 -mediated signaling (e.g., as determined using assays such as those described in Example 6).

[0117] In some embodiments, the anti-IL21R antibody or antigen-binding portion inhibits B cell proliferation induced by IL21 signaling (e.g., as determined using assays such as those described in Example 6).

[0118] In some embodiments, the anti-IL21R antibody or antigen-binding portion inhibits IL21-induced p-STATl, p-STAT3, and / or p-STAT5 signaling (such as the signaling of all three) in primary B cells (e.g., at a concentration of 66.6 nM and / or 330 nM) (e.g., as determined using assays such as those described in Example 7).

[0119] In some embodiments, the anti-IL21R antibody or antigen-binding portion blocks differentiation of IgG-, IgA-, and / or IgE-secreting plasma cells (such as differentiation of all three) from PBMCs (e.g., as determined using assays such as those described in Example 8).

[0120] In some embodiments, the anti-IL21R antibody or antigen-binding portion increases iTreg differentiation inhibited by the IL21 pathway, e.g., with a potency of 5, 4, 3, 2, or 1 nM or less (e.g., 1 nM or less) (e.g., as determined using assays such as those described in Example 9). In certain embodiments, iTreg differentiation is restored to baseline levels.

[0121] In some embodiments, the anti-IL21R antibody or antigen-binding portion does not induce antibody-dependent cellular cytotoxicity (ADCC) (e.g., as determined using assays such as those described in Example 10).

[0122] In some embodiments, the anti-IL21R antibody or antigen-binding portion is non-polyreactive in DNA and / or insulin ELISA assays (e.g., as determined using assays such as those described in Example 11). In certain embodiments, the anti-IL21R antibody or antigenbinding portion is less polyreactive than ATR-107 and / or C2, e.g. in DNA and / or insulinELISA assays. In certain embodiments, the anti-IL21R antibody or antigen-binding portion is less polyreactive than ATR-107 antibody, e.g. in DNA and / or insulin ELISA assays. In certain embodiments, the anti-IL21R antibody or antigen-binding portion is less polyreactive than C2 antibody, e.g. in DNA and / or insulin ELISA assays. In certain embodiments, the anti-IL21R antibody or antigen-binding portion is less polyreactive than ATR-107 and C2 antibodies, e.g. in DNA and / or insulin ELISA assays. In some embodiments ATR-107 is defined as comprising a HC sequence comprising or consisting of SEQ ID NO: 45, and a LC sequence comprising or consisting of SEQ ID NO: 46. In some embodiments C2 is defined as comprising a HC sequence comprising or consisting of SEQ ID NO: 51, and a LC sequence comprising or consisting of SEQ ID NO: 52.

[0123] In some embodiments, the anti-IL21R antibody or antigen-binding portion suppresses GvHD in vivo, for example inhibiting development of GvHD in PBMC-transplanted NRG mice (e.g., as determined using assays such as those described in Example 12). In certain embodiments, the anti-IL21R antibody or antigen-binding portion reduces one or more symptoms of GvHD, such as weight loss, anemia, reduced activity, hair loss, posture, and reduced mortality. In certain embodiments, the anti-IL21R antibody or antigen-binding portion decreases CD8+cytotoxic T cells, increases CD4+T cells, increases CD25+FoxP3+regulatory T cells, or any combination thereof.

[0124] In some embodiments, the anti-IL21R antibody or antigen-binding portion has a half-life (ti / 2) of at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 hours e.g., at least 170 hours or at least 190 hours) (e.g., as determined using assays such as those described in Example 13). In certain embodiments, the anti-IL21R antibody or antigenbinding portion does not induce anti -drug antibodies.

[0125] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to domain I on the extracellular domain of IL21R. In certain embodiments, the anti-IL21R antibody or antigen-binding portion does not bind to domain II of IL21R.

[0126] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to an epitope of IL21Rthat overlaps with the binding site of IL21. In certain embodiments, binding of the antibody induces a conformational change in a loop comprising residues 33-43 of IL21R, a region essential to cytokine binding.

[0127] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to IL21R with a binding interface formed by LCDR1, LCDR3, and HCDR2.

[0128] In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to an epitope of the extracellular domain (ECD) of IL21R (residues 20-232) that includes oneor more residues selected from D34, Y36, E37, H68, D72, S92, and E97 (e.g., as determined using assays such as those described in Example 14). In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to an epitope of the ECD of IL21R that comprises one or more residues selected from D34, Q35, Y36, E37, E38, H68, F69, M70, A71, D72, 174, S92, L94, A96, E97, and S190 (e.g., comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all 16 of said residues). In certain embodiments, the epitope comprises or consists of residues D34, Q35, Y36, E37, E38, H68, F69, M70, A71, D72, 174, S92, L94, A96, E97, and SI 90. In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to an epitope of the ECD of IL21R that comprises one or more residues selected from D53, Y55, E56, H87, D91, Sill, and El 16 (e.g., comprises 1, 2, 3, 4, 5, 6, or all 7 of said residues).

[0129] For example, the anti-IL21R antibody or antigen-binding portion may bind to an epitope of IL21Rthat includes- residues E97, D72, D34, and H68;- residues Y36, E37, D72, and S92;or any combination thereof.

[0130] In some embodiments, an anti-IL21R antibody or antigen-binding portion herein binds specifically to an epitope of the ECD of IL21R that comprises or consists of residues D34, Y36, E37, H68, D72, S92, E97, and S190. In some embodiments, the anti-IL21R antibody or antigen-binding portion binds to IL21R with a binding interface formed by LCDR1, LCDR3, and HCDR2, and by residues D34, Y36, E37, H68, D72, S92, E97, and SI 90 of the ECD of IL21R. In some embodiments, an anti-IL21R antibody or antigenbinding portion herein binds specifically to an epitope of the ECD of IL21R that comprises or consists of residues D34, Q35, Y36, E37, E38, H68, F69, M70, A71, D72, 174, S92, L94, A96, E97, and SI 90.

[0131] The numbering of the residues is in reference to the IL21R ECD, and begins with residue 20 of SEQ ID NO: 57 (human IL21R) as residue 1 of the ECD. Accordingly, with reference to SEQ ID NO: 57, the above residues are numbered as follows:IL21R ECD SEQ ID NO: 57Residue ResidueD34 D53Q35 Q54Y36 Y55E37 E56E38 E57H68 H87F69 F88M70 M89A71 A90D72 D91174 193S92 SillL94 L113A96 A115E97 E116S190 S209

[0132] In some embodiments, an anti-IL21R antibody or antigen-binding portion thereof binds to the same epitope as a reference antibody having a heavy chain variable domain (VH) and a light chain variable domain (VL) comprising SEQ ID NOs: 1 and 2, respectively, and the epitope comprises or consists of all of amino acids D53, Y55, E56, H87, D91, Sill, and El 16 of SEQ ID NO: 57. In some embodiments, the epitope comprises or consists of all of amino acids D53, Q54, Y55, E56, E57, H87, F88, M89, A90, D91, 193, Sill, LI 13, Al 15, El 16, and S209 of SEQ ID NO: 57.

[0133] An anti-IL21R antibody or antigen-binding portion with any combination of the above properties is also contemplated.

[0134] In some embodiments, the present disclosure provides an anti-IL21R binding protein that comprises, or has the binding specificity of, the anti-IL21R antibody or antigenbinding portion described herein. In some embodiments, the binding protein is a multispecific (e.g., bispecific) binding molecule that has the binding specificity of an anti-IL21R antibody described herein (e.g., may comprise a binding portion with the six CDRs or the VH and VL of said anti-IL21R antibody). In some embodiments, the multispecific binding molecule additionally has the binding specificity of a) another, distinct anti-IL21R antibody, e.g., an antibody that targets different epitope(s) on the same protein(s), or b) another, distinct antibody that targets a different protein, such as another cell surface molecule whose activity mediates the immune response or a disease condition such as an inflammatory or autoimmune disease. Multispecific binding molecules are known in the art, and examples of different types of multispecific binding molecules (e.g., bispecific binding molecules) are given elsewhere herein.

[0135] In some embodiments, the anti-IL21R binding protein is a fusion antibody or an immunoadhesin.

[0136] In some embodiments, the anti-IL21R binding protein is an immunoconjugate, wherein the anti-IL21R antibody or antigen-binding portion thereof is conjugated to another molecule, e.g., a therapeutic moiety. Examples of immunoconjugates include antibody-drugconjugates and antibody -toxin fusion proteins.

[0137] In some embodiments, the anti-IL21R binding protein is a small modular immunopharmaceutical (SMIP).II. Nucleic Acid Molecules and Vectors

[0138] The present disclosure also provides nucleic acid molecules and sequences encoding anti-IL21R antibodies or antigen-binding portions thereof described herein, or binding proteins described herein. In some embodiments, different nucleic acid molecules encode the heavy chain and light chain amino acid sequences of the anti-IL21R antibody or antigen-binding portion. In other embodiments, the same nucleic acid molecule encodes the heavy chain and light chain amino acid sequences of the anti-IL21R antibody or antigenbinding portion.

[0139] A reference to a nucleotide sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. The term “polynucleotide” as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide. The term includes single- and double-stranded forms.

[0140] In some embodiments, the present disclosure provides a nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain sequence, or a nucleotide sequence that encodes the light chain sequence, or both, of an anti-IL21R antibody or antigen-binding portion thereof described herein. In some embodiments, the present disclosure provides a set (e.g., a pair) of nucleic acid molecules comprising a nucleotide sequence that encodes the heavy chain sequence, and a nucleotide sequence that encodes the light chain sequence, of an anti-IL21R antibody or antigen-binding portion thereof described herein.

[0141] The present disclosure also provides nucleotide sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to one or more nucleotide sequences recited herein, e.g., to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 9, 10, 19, 20, 29, 30, 39, and 40. The term “percent sequence identity” in the context of nucleic acid sequences refers to the residues in two sequences that are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides, usually at least about 18 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at leastabout 32 nucleotides, and preferably at least about 36, 48, or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wisconsin. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (see, e.g., Pearson, Methods Enzymol.(1990) 183:63-98; Pearson, Methods Mol. Biol. (2000) 132:185-219; Pearson, Methods Enzymol. (1996) 266:227-58 (1996); and Pearson, J. Mol. Biol. (1998) 276:71-84; incorporated herein by reference).

[0142] In some embodiments, the present disclosure provides a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 9, 10, 19, 20, 29, 30, 39, 40, 70, 71, 72, 73, 74, 75, 76, and 77.

[0143] In some embodiments, the present disclosure provides a nucleic acid molecule or a set (e.g., a pair) of nucleic acid molecules comprising the nucleotide sequences of a) SEQ ID NOs: 9 and 10;b) SEQ ID NOs: 19 and 20;c) SEQ ID NOs: 29 and 30;d) SEQ ID NOs: 39 and 40;e) SEQ ID NOs: 70 and 71;f) SEQ ID NOs: 72 and 73;g) SEQ ID NOs: 74 and 75;h) SEQ ID NOs: 76 and 77;i) SEQ ID NOs: 78 and 84;j) SEQ ID NOs: 79 and 85;k) SEQ ID NOs: 80 and 86;l) SEQ ID NOs: 81 and 87;m) SEQ ID NOs: 82 and 88;n) SEQ ID NOs: 83 and 89.

[0144] In any of the above embodiments, the nucleic acid molecules may be isolated. Nucleic acid molecules referred to herein as “isolated” or “purified” are nucleic acids which (1) have been separated away from the nucleic acids of the genomic DNA or cellular RNA of their source of origin; and / or (2) do not occur in nature.

[0145] In a further aspect, the present disclosure provides a vector suitable for expressingone or both of the chains of an antibody or antigen-binding portion thereof as described herein. The term “vector”, as used herein, means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In some embodiments, the vector is a plasmid, i.e., a circular double stranded piece of DNA into which additional DNA segments may be ligated. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”).

[0146] The present disclosure provides vectors comprising nucleic acid molecules that encode the heavy chain sequence, the light chain sequence, or both the heavy and light chain sequences, of an anti-IL21R antibody or antigen-binding portion thereof as described herein. In certain embodiments, a vector of the present disclosure comprises a nucleic acid molecule described herein, or a pair or set of nucleic acid molecules described herein. In certain embodiments, the present disclosure provides a set (e.g., a pair) of vectors comprising a set or pair of nucleic acid molecules described herein. The present disclosure further provides vectors comprising nucleic acid molecules encoding binding proteins, fusion proteins, modified antibodies, etc. as described herein. The vectors may further comprise an expression control sequence.

[0147] The term “expression control sequence” as used herein means polynucleotide sequences that are necessary to effect the expression and processing of coding sequences to which they are ligated. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The term “control sequences” is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.III. Making of Antibodies and Binding Proteins

[0148] The anti-IL21R antibodies and antigen-binding portions thereof of the present disclosure, or related binding proteins as described herein, may be produced recombinantly using isolated nucleic acid molecules such as expression constructs. The encoding sequencesfor each polypeptide chain may be cloned into a single vector or cloned into separate vectors (e.g., a pair or set of vectors).

[0149] The antibodies or antigen-binding portions thereof or binding proteins may be produced in host cells, e.g., mammalian host cells (such as KMS11 or RAJI), using appropriate expression constructs. Mammalian cell lines available as hosts for expression include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, inter alia, Chinese hamster ovary (CHO) cells, NSO cells, SP2 cells, HEK-293T cells, 293 Freestyle cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, and a number of other cell lines. Other cell lines that may be used are insect cell lines, such as Sf9 or Sf21 cells, and yeast cell lines. In certain embodiments, the cell lines are not derived from a human embryo. Cell lines may be selected based on their expression levels. The antibodies, antigen-binding portions, or binding proteins may be isolated and purified from the host cell culture using well known methods, such as centrifugation, ultracentrifugation, protein A, protein G, protein A / G, or protein L purification, and / or ion exchange chromatography.

[0150] In some embodiments, a host cell described herein comprises nucleic acid molecule(s) comprising a nucleotide sequence that encodes the heavy chain sequence, or a nucleotide sequence that encodes the light chain sequence, or both, of an anti-IL21R antibody or antigen-binding portion thereof described herein. In certain embodiments, the host cell comprises nucleic acid molecule(s) encoding both the heavy and light chain sequences. In certain embodiments, the host cell comprises nucleic acid molecule(s) encoding only the heavy or light chain sequence, such chains being useful, e.g., as intermediates for the expression of an antibody or antigen-binding fragment that includes said heavy or light chain.

[0151] Host cells used to produce the antibodies, antigen-binding portions, or binding proteins are also termed “recombinant host cells.” A “recombinant host cell” (or simply “host cell”), as used herein, means a cell into which a recombinant expression construct has been introduced. By definition, a recombinant host cell does not occur in nature. A protein produced from a recombinant host cell is a recombinant protein.IV. Pharmaceutical Compositions and Uses

[0152] Another aspect of the present disclosure is a pharmaceutical composition comprising as an active ingredient (or as the sole active ingredient) an anti-IL21R antibody or antigen-binding portion thereof or binding protein of the present disclosure. Thepharmaceutical composition may additionally comprise a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” may include appropriate solvents, dispersion media, antibacterial and antifungal agents, isotonic agents, and the like. Examples of pharmaceutically acceptable excipients are water and saline (e.g., phosphate-buffered saline).

[0153] The pharmaceutical compositions herein may be used to treat an inflammatory or autoimmune disease. In some embodiments, a method of treating a disease (such as an inflammatory or autoimmune disease) in a subject comprises administering to the subject a therapeutically effective amount of an antibody or antigen-binding portion, binding protein, or pharmaceutical composition disclosed herein. In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of graft-versus-host disease (GvHD), asthma, allergic asthma, chronic spontaneous urticaria (CSU), diabetes (e.g., type 1 diabetes or latent autoimmune diabetes), lupus (e.g., systemic lupus erythematosus or lupus nephritis), arthritis (e.g., rheumatoid arthritis or juvenile arthritis), giant cell arteritis, allergy, antibody-mediated rejection, organ graft rejection, transplant desensitization, Addison’s disease, ankylosing spondylitis, anti -glomerular basement membrane disease, IgA nephropathy, autoimmune hepatitis, primary biliary cholangitis (PBC), celiac disease, autoimmune alopecia, atopic dermatitis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, granulomatosis with polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, autoimmune thyroid disease (AITD), antiphospholipid syndrome, hemolytic anemia, Henoch-Schonlein purpura, juvenile myositis, Kawasaki disease, inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), multiple sclerosis, myasthenia gravis, neuromyelitis optica, psoriasis, psoriatic arthritis, Sjogren’s syndrome, systemic scleroderma, systemic sclerosis, immune thrombocytopenia (ITP), thrombocytopenic purpura, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, uveitis, autoimmune uveitis, thyroid eye disease, vasculitis, vitiligo, neuromyelitis optica spectrum disorder (NMOSD), encephalitis, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), and Vogt-Koyanagi-Harada Disease.

[0154] In certain embodiments, the antibodies or antigen-binding portions thereof, compositions, or binding proteins of the present disclosure may be used to treat graft-versus-host disease (GvHD).

[0155] In certain embodiments, the antibodies or antigen-binding portions thereof, compositions, or binding proteins of the present disclosure may be used to treat pemphigusvulgaris, autoimmune hepatitis, vitiligo, antibody-mediated rejection, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

[0156] The pharmaceutical compositions herein may be used to treat cancer. In some embodiments, a method of treating cancer in a subject comprises administering to the subject a therapeutically effective amount of an antibody or antigen-binding portion, composition, or binding protein disclosed herein. The cancer may be in one or more tissues such as skin, lung, intestine, colon, ovary, brain, prostate, kidney, soft tissues, the hematopoietic system, head and neck, liver, bone, bladder, breast, stomach, uterus, cervix, and pancreas. In particular embodiments, the cancer may be multiple myeloma or diffuse large B cell lymphoma (DLBCL).

[0157] Treat,” “treating,” and “treatment” refer to a method of alleviating or abrogating a biological disorder and / or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and / or occurrence frequency of the symptoms of the disease, disorder, or condition.“Therapeutically effective amount” refers to the amount of the therapeutic agent being administered that will relieve to some extent one or more of the symptoms of the disorder being treated. For example, a therapeutically effective amount of an anti-cancer therapeutic may, for example, result in delayed tumor growth, elimination of cancer cells, tumor shrinkage, increased survival, slowed or decreased metastasis, or other clinical endpoints desired by healthcare professionals.

[0158] The anti-IL21R antibodies or antigen-binding portions thereof, antibody compositions, or binding proteins of the present disclosure may be administered without additional therapeutic treatments, i.e., as a stand-alone therapy (monotherapy). Alternatively, treatment with the anti-IL21R antibodies or antigen-binding portions thereof, antibody compositions, or binding proteins of the present disclosure may include at least one additional therapeutic treatment (combination therapy), e.g., another immunomodulatory agent.

[0159] The pharmaceutical compositions herein may be delivered to the patient through parenteral administration. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrathecal, or intravenous injection (e.g., intravenous infusion). Particular embodiments include the intravenous route (e.g., intravenous infusion) and the subcutaneous route (e.g., subcutaneous injection).V. Diagnostic Uses

[0160] The antibodies and antigen-binding portions or binding proteins of the presentdisclosure also are useful in diagnostic processes (e.g., in vitro or ex vivo). For example, the antibodies, antigen-binding portions, or binding proteins can be used to detect and / or measure the level of IL21R in a biological sample from a patient (e.g., a tissue sample, or a blood sample). Suitable detection and measurement methods include immunological methods such as flow cytometry, enzyme-linked immunosorbent assays (ELISA), chemiluminescence assays, radioimmunoassays, and immunohistochemistry. The present disclosure further encompasses kits (e.g., diagnostic kits) comprising the antibodies, antigen-binding portions, or binding proteins described herein.

[0161] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

[0162] According to the present disclosure, back-references in the dependent claims are meant as short-handwriting for a direct and unambiguous disclosure of each and every combination of claims that is indicated by the back-reference. Any compound disclosed herein can be used in any of the treatment method here, wherein the individual to be treated isas defined anywhere herein. Further, headers herein are created for ease of organization and are not intended to limit the scope of the claimed invention in any manner.

[0163] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.EXAMPLESExample 1: Generation of Anti-IL21R Antibodies from Rat B Cells

[0164] Antibodies against human IL21R were isolated from an antibody repertoire derived from OmniRat® rats (Osborn et al., J Immunol. (2013) 190(4): 1481-90), a transgenic rat strain from Ligand Pharmaceuticals Inc. that produces antibodies with fully human idiotypes. Cloning of rat-derived antibody genes from single-cell sorted antibody-secreting B cells (ASC) was performed by means of Symplex™ antibody discovery technology (Meijer et al., J Mol Biol. (2006) 358(3):764-72).

[0165] Antibody repertoire constructs encoding fully human immunoglobulins in IgGi-LALA format (see below) were transfected into HEK293 cells. Cell culture supernatants were screened for binding to IL21R expressed on the surface of transfected CHO cells using flow cytometry in a high-throughput format. IL21R reactive clones were analyzed by DNA sequencing and antibody-encoding DNA sequences were extracted. Selected antibody clones were sequence corrected, expressed in CHO cells, purified by Protein A chromatography, and tested functionally as described below.

[0166] Missense mutations in the amino termini of heavy and light chains that were introduced by the use of degenerate primers in the Symplex™ cloning of the antibodyencoding cDNA fragments were corrected back to germline sequence (“germlined”). Table 1 shows the heavy and light chain variable domain nucleotide sequences of the germlined antibodies designated 33628, 32302, 33726, and 33733. The correction process involved amino terminal sequence correction to germline as well as codon usage optimization. The targets for matching to human germline sequences were identified by BLAST® homology searches for the heavy chain and light chain variable regions.Table 1: Anti-IL21R Antibody Variable Domain Nucleotide Sequences Description Sequence (5' to 3 ) SEQ ID NO CAGCTGCAGCTGCAGGAGTCTGGCCCAGGACTGGTGAAGCCAAG CGAGACCCTGTCTCTGACCTGCACAGTGTCCGGCGGCAGCATCT CCAGCTCTTCCTACTATTGGGGATGGATCAGGCAGCCACCTGGC AAGGGCCTGGAGTGGTTCGGCTCCATCAGCTACTCTGGCAGAAC33628 VHATACTATAACCCCTCTCTGAAGTCCCGCGTGACCATTAGTGTGG 9 ACACAAGCAAGAATCAGTTCTCCCTGAAGCTGAGCTCTGTGACC GCCGCTGATACAGCCGTGTACTATTGTGCTAGGAGGGAGGCCGC TGCCGGAACCGGCTTTGACTATTGGGGCCAGGGCACCCTGGTGA CAGTCTCGAGT GAGATCGTGCTGACCCAGACACCAGCCACCCTGAGCCTGTCTCC AGGAGAGAGAGCCACACTGTCTTGCCGCGCTTCCCAGAGCGTGT CCAGCTTCCTGGCTTGGTACCAGCAGAAGCCAGGACAGGCTCCT AGGCTGCTGATCTATGACGCCTCCAACAGGGCTACCGGCATCCC33628 VLTGCTCGTTTCTCTGGTTCCGGCAGCGGCACAGACTTTACCCTGA 10 CAATCTCTTCCCTGGAGCCAGAGGATTTCGCCGTGTACTATTGT CAGCAGAGGAGCCGGACCTTTGGCCAGGGCACAAAGGTGGAGAT CAAG GAGGTGCAGCTGCTGGAGAGCGGAGGAGGACTGGTGCAGCCAGG AGGCAGCCTGAGGCTGTCTTGCGCCGCTTCCGGCTTCACTTTTA GTAGCTATGCTATGTCTTGGGTGAGACAGGCTCCTGGCAAGGGC CTGGAGTGGGTGTCCGCCATCTCTGGCTCCGGAGGCTCCACATA32302 VHCTATGCTGATAGCGTGAAGGGCAGATTCACCATCAGCCGCGACA 19 ACTCTAAGAATACACTGTACCTGCAGATGAACTCTCTGAGGGCC GAGGACACCGCCGTGTACTATTGTGCCAAGAGGGATCGGATCGT GGGCGCCACCACAGCTTTTGACTATTGGGGCCAGGGCACCCTGG TGACAGTCTCGAGT GACATCCAGATGACCCAGAGCCCCTCCTCCGTGTCCGCCTCCGT GGGCGATAGGGTGACCATCACATGCCGGGCCTCTCAGGTCATCA GAAACTGGCTGGCTTGGTACCAGCAGAAGCCCGGCAAGGCCCCT AAGCTGCTGATCTATGCCGCTTCTAGTCTTCAGTCTGGAGTTCC32302 VLATCCCGCTTCTCTGGCTCCGGCAGCGGAACAGACTTTACCCTGA 20 CAATCAGCTCTCTGCAGCCAGAGGATTTCGCCACCTACTATTGT CAGCAGACAAATTCCTTCCCCCTGACCTTTGGCCAGGGCACAAA GGTGGAGATCAAG GAGGTGCAGCTGGTGGAGTCCGGAGGCGACCTGGTGCAGCCAGG AGGCAGCCTGAGGCTGTCTTGCGCCGCTTCCGGCTTCACTTTTA GCACATATAATATGAATTGGGTGAGACAGGCTCCTGGCAAGGGC CTGGAGTGGATTTCTTATATCTCCTTCAGTAGCGCCAGCATTTT33726 VHTTATGCTGGTTCTGTTAAGGGCAGGTTCACCATCTCCCGGGACA 29 AC GC C AAG AAT AGT CT T T AT CT GC AAAT GAAC T C T C T GAG AG AC GAGGATACAGCCGTGTACTATTGTGCTCGCCTGGTGGGCGCCCC AGATTATTGGGGCCAGGGCACCCTGGTGACAGTCTCGAGT GACGTGGTCATGACCCAGAGCCCACTGTCTCTGCCCGTGACACT GGGCCAGCCAGCCTCTATCTCCTGCAGGTCCAGCCAGTCCCTGG TGTACAGCGATGGCAACACCTATCTGAATTGGTTCCAGCAGAGA CCTGGCCAGAGCCCAAGGCGGCTGATCTACAAGGTGTCTAACAG33726 VLAGACTCCGGAGTGCCAGATCGCTTCAGCGGCTCTGGCTCCGGAA 30 CCGACTTTACACTGAAGATTTCTCGTGTTGAGGCTGAGGATGTG GGCGTGTACTATTGTATGCAGGGCACCCACTGGCCCCCTACCTTCACATTTGGCCCTGGCACAAAGGTGGACATCAAGDescription Sequence (5' to 3 ) SEQ ID NO GAGGTGCAGCTGGTGCAGAGCGGAGCTGAGGTGAAGAAGCCAGG CGAGTCCCTGAAGATCAGCTGCAAGGGCTCCGGCTACAGCTTCA CCTCTTATTGGATTGGTTGGGTTAGACAGATGCCAGGAAAGGGC CTTGAATGGATGGGAACCATCTACCCCGGCGACTCTGATACACG33733 VHCTATAGTCCTAGTTTCCAAGGTCAGGTTACCATCTCCGCCGACA 39AGAGCATCTCTACAGCTTTTCTTCAATGGAGTAGCCTGAAGGCC TCTGATACAGCTATGTACTATTGTGCCATCAAGGGCAGGTACCG GACCGCTTTTGACATCTGGGGCCAGGGCACCACAGTGACAGTCT CGAGT GACATCGTGATGACCCAGTCCCCACTGTCTCTGTCCGTGACACC AGGACAGCCTGCCAGCATCTCTTGCAAGTCCAGCCAGTCCCTGC TGCACAGCAACGGCTACAATTATCTGGGTTGGTATCTTCAAAAG CCAGGCCAGAGCCCCCAGTTCCTGATCTATCTGGGCTCTAACAG33733 VLGGCTTCCGGAGTGCCTGACAGGTTCTCCGGCAGCGGCTCTGGAA 40CCGATTTCACTCTTAAGATTTCTAGGGTTGAGGCCGAGGATGTG GGCGTGTACTATTGTATGCAGGCTCTGCAGACCCCATACACATTTGGCCAGGGCACCAAGCTGGAGATCAAG

[0167] Amino acid sequences of the variable domains of antibodies 33628, 32302, 33726, and 33733 are shown in Table 2, where the CDRs annotated according to the IMGT® system are underlined.Table 2: Anti-IL21R Antibody Variable Domain Amino Acid Sequences Description Sequence (N-terminal to C-terminal) SEQ ID NO QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPG33628 VHKGLEWFGSISYSGRTYYNPSLKSRVTISVDTSKNQFSLKLSSVT 1AADTAVYYCARREAAAGTGFDYWGQGTLVTVSS EIVLTQTPATLSLSPGERATLSCRASQSVSSFLAWYQQKPGQAP33628 VLRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC 2QQRSRT FGQGT KVE I K EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKG32302 VHLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRA 11EDTAVYYCAKRDRIVGATTAFDYWGQGTLVTVSS DIQMTQSPSSVSASVGDRVTITCRASQVIRNWLAWYQQKPGKAP32302 VLKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 12QQTNSFPLTFGQGT KVE I K EVQLVESGGDLVQPGGSLRLSCAASGFTFSTYNMNWVRQAPGKG33726 VHLEWI SY ISFSSASI FYAGSVKGRFT I SRDNAKNSLYLQMNSLRD 21EDTAVYYCARLVGAPDYWGQGTLVTVSS D VVMT Q S P L S L P VT LGQ P AS I S C R S S QSLVYSDGNTYLNW FQ Q R33726 VLPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDV 22GVY Y CMQGTHWPPTFT FG PGT KVD I K EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKG33733 VHLE WMGT IYPGDSDTRY S P S FQGQVT I SADKS I ST AFLQWS SLKA 31SDTAMYYCAIKGRYRTAFDIWGQGTTVTVSS DIVMTQSPLSLSVTPGQPASISCKSSQSLLHSNGYNYLGWYLQK33733 VLPGQSPQFLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDV 32GVYYCMQALQTPYTFGQGTKLEIK

[0168] Amino acid sequences of the complementarity-determining regions (CDRs) of antibodies 33628, 32302, 33726, and 33733 as defined by the IMGT® system are shown in Table 3, with SEQ ID NOs under each sequence in parentheses.Table 3: Anti-IL21R Antibody CDR Amino Acid SequencesSequenceAntibodyHCDR1 HCDR2 HCDR3 LCDR1 LCDR2 LCDR3 GGSISSSSYY ISYSGRT ARREAAAGTGFDY QSVSSF DAS QQRSRT33628( 3 ) ( 4 ) ( 5) ( 6) (7 ) ( 8 ) GFTFSSYA ISGSGGST AKRDRIVGATTAFDY QVIRNW AAS QQTNSFPLT32302( 13 ) ( 14) ( 15) ( 16) ( 17 ) ( 18 )QSLVYS GFTFSTYN ISFSSASI ARLVGAPDY KVS MQGTHWPPTFT33726 DGNTY(23 ) (24) ( 25) (27 ) (28 )( 26)QSLLHS GYSFTSYW IYPGDSDT AIKGRYRTAFDI LGS MQALQTPYT33733 NGYNY(33 ) (34) ( 35) (37 ) (38 )( 36)

[0169] Amino acid sequences and select nucleotide sequences of heavy and light chain constant regions (CH and CL, respectively) for antibodies 33628, 32302, 33726, and 33733 are shown in Table 4. “IgGi-3f’ refers to the presence of L234A, L235E, and G237A mutations in the heavy chain (numbered according to the Eu numbering scheme), which are known to reduce effector function of the Fc region of IgGi antibodies (Gross et al., Immunity (2001) 15(2):282-302). “IgGi LALA” refers to the presence of “LALA” mutations in the heavy chain (L234A / L235A, numbered according to the IMGT® numbering scheme) that are known to reduce effector function of the Fc region of IgGi antibodies (Hezareh et al., J Virol.75(24): 12161-68 (2001); Hessell et al., Nature 449(7158): 101-04 (2007)). Unless otherwise specified, the antibodies in the experiments herein are in IgGi-3f format.Table 4: Constant Region SequencesFragment Sequence SEQ ID NO Amino Acid Sequences (N-terminal to C-terminal) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTIgGi CH 41 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKIgGi- PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT42 LALA CH KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTIgGi-3fCH 43 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVKappa CL DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA 44CEVTHQGLSSPVTKSFNRGECFragment Sequence SEQ ID NO Nucleotide Sequences (5' to 3 ) GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCT CCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT CAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAAT CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCA AATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACC TGAAGCCGAAGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAA CCCAAGGACACCCTGATGATCTCCCGGACCCCTGAGGTCACAT GCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAIgGi-3fCHAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA 60 GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCAC AGGTGTACACCCTGCCCCCATCCCGCGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACA ACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTT CTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGC ACAACCACTACACGCAGAAAAGCCTCTCCCTGTCCCCCGGTAA A CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTG GATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGKappa CL AGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCT 61 GACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0170] Table 5 shows the nucleotide and amino acid sequences of the heavy and light chains for antibodies 33628, 32302, 33726, and 33733.Table 5: Anti-IL21R Antibody Heavy and Light Chain Sequences Description Sequence SEQ ID NO Amino Acid Sequences (N-terminal to C-terminal) QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPG KGLEWFGSISYSGRTYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYYCARREAAAGTGFDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE33628 HC PKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVT 62 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK EIVLTQTPATLSLSPGERATLSCRASQSVSSFLAWYQQKPGQAP RLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC33628 LC QQRSRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL 63 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKG LEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCAKRDRIVGATTAFDYWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV32302 HC EPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEV 64 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK DIQMTQSPSSVSASVGDRVTITCRASQVIRNWLAWYQQKPGKAP KLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC32302 LC QQTNSFPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV 65 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EVQLVESGGDLVQPGGSLRLSCAASGFTFSTYNMNWVRQAPGKG LEWISYISFSSASIFYAGSVKGRFTISRDNAKNSLYLQMNSLRD EDTAVYYCARLVGAPDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD33726 HC KTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVD 66 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQR PGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDV GVYYCMQGTHWPPTFTFGPGTKVDIKRTVAAPSVFIFPPSDEQL33726 LC KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 67DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDescription Sequence SEQ ID NO EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKG LEWMGTIYPGDSDTRYSPSFQGQVTISADKSISTAFLQWSSLKA SDTAMYYCAIKGRYRTAFDIWGQGTTVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK33733 HC SCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCV 68 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK DIVMTQSPLSLSVTPGQPASISCKSSQSLLHSNGYNYLGWYLQK PGQSPQFLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDV33733 LC GVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS 69 GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECNucleotide Sequences (5' to 3' ) CAGCTGCAGCTGCAGGAGTCTGGCCCAGGACTGGTGAAGCCAAG CGAGACCCTGTCTCTGACCTGCACAGTGTCCGGCGGCAGCATCT CCAGCTCTTCCTACTATTGGGGATGGATCAGGCAGCCACCTGGC AAGGGCCTGGAGTGGTTCGGCTCCATCAGCTACTCTGGCAGAAC ATACTATAACCCCTCTCTGAAGTCCCGCGTGACCATTAGTGTGG ACACAAGCAAGAATCAGTTCTCCCTGAAGCTGAGCTCTGTGACC GCCGCTGATACAGCCGTGTACTATTGTGCTAGGAGGGAGGCCGC TGCCGGAACCGGCTTTGACTATTGGGGCCAGGGCACCCTGGTGA CAGTCTCGAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTG GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT GTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGAC CGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACG T G AAT C AC AAGC CC AGC AAC AC C AAGGT GG AC AAGAGAGT T GAG33628 HC CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGC 70 ACCTGAAGCCGAAGGGGCACCGTCAGTCTTCCTCTTCCCCCCAA AACCCAAGGACACCCTGATGATCTCCCGGACCCCTGAGGTCACA TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG TACACCCTGCCCCCATCCCGCGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTA TAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAAAGCCTCTCCCTGTCCCCCGGTAAADescription Sequence SEQ ID NO GAGATCGTGCTGACCCAGACACCAGCCACCCTGAGCCTGTCTCC AGGAGAGAGAGCCACACTGTCTTGCCGCGCTTCCCAGAGCGTGT CCAGCTTCCTGGCTTGGTACCAGCAGAAGCCAGGACAGGCTCCT AGGCTGCTGATCTATGACGCCTCCAACAGGGCTACCGGCATCCC TGCTCGTTTCTCTGGTTCCGGCAGCGGCACAGACTTTACCCTGA CAATCTCTTCCCTGGAGCCAGAGGATTTCGCCGTGTACTATTGT CAGCAGAGGAGCCGGACCTTTGGCCAGGGCACAAAGGTGGAGAT33628 LC CAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCAT 71 CTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGT GGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAG AGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTG AC GC T G AGO AAAGC AG AC T ACG AG AAAC AC AAAGT C T AC GC CT G CGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGT GAGGTGCAGCTGCTGGAGAGCGGAGGAGGACTGGTGCAGCCAGG AGGCAGCCTGAGGCTGTCTTGCGCCGCTTCCGGCTTCACTTTTA GTAGCTATGCTATGTCTTGGGTGAGACAGGCTCCTGGCAAGGGC CTGGAGTGGGTGTCCGCCATCTCTGGCTCCGGAGGCTCCACATA CTATGCTGATAGCGTGAAGGGCAGATTCACCATCAGCCGCGACA ACTCTAAGAATACACTGTACCTGCAGATGAACTCTCTGAGGGCC GAGGACACCGCCGTGTACTATTGTGCCAAGAGGGATCGGATCGT GGGCGCCACCACAGCTTTTGACTATTGGGGCCAGGGCACCCTGG TGACAGTCTCGAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC CTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCT GGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCA ACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT32302 HC GAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC 72 AGCACCTGAAGCCGAAGGGGCACCGTCAGTCTTCCTCTTCCCCC CAAAACCCAAGGACACCCTGATGATCTCCCGGACCCCTGAGGTC ACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAA GTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCG AGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG GTGTACACCCTGCCCCCATCCCGCGAGGAGATGACCAAGAACCA GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCT CTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGA ACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAAAGCCTCTCCCTGTCCCCCGGTAAADescription Sequence SEQ ID NO GACATCCAGATGACCCAGAGCCCCTCCTCCGTGTCCGCCTCCGT GGGCGATAGGGTGACCATCACATGCCGGGCCTCTCAGGTCATCA GAAACTGGCTGGCTTGGTACCAGCAGAAGCCCGGCAAGGCCCCT AAGCTGCTGATCTATGCCGCTTCTAGTCTTCAGTCTGGAGTTCC ATCCCGCTTCTCTGGCTCCGGCAGCGGAACAGACTTTACCCTGA CAATCAGCTCTCTGCAGCCAGAGGATTTCGCCACCTACTATTGT CAGCAGACAAATTCCTTCCCCCTGACCTTTGGCCAGGGCACAAA32302 LC GGTGGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCT 73 TCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTT GTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACA GTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GT GT CACAGAGC AGGACAGC AAGGAC AGCACCT ACAGCCT CAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGT CTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCA C AAAGAGC T T C AAC AGGGGAGAGT GT GAGGTGCAGCTGGTGGAGTCCGGAGGCGACCTGGTGCAGCCAGG AGGCAGCCTGAGGCTGTCTTGCGCCGCTTCCGGCTTCACTTTTA GCACATATAATATGAATTGGGTGAGACAGGCTCCTGGCAAGGGC CTGGAGTGGATTTCTTATATCTCCTTCAGTAGCGCCAGCATTTT TTATGCTGGTTCTGTTAAGGGCAGGTTCACCATCTCCCGGGACA AC GC C AAG AAT AGT CT T T AT CT GC AAAT GAAC T C T C T GAG AG AC GAGGATACAGCCGTGTACTATTGTGCTCGCCTGGTGGGCGCCCC AGATTATTGGGGCCAGGGCACCCTGGTGACAGTCTCGAGTGCCT CCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC TGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAG CTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGAC337267HC AAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGG 74 GGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCC TGATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC AGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC CAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAG CCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA TCCCGCGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCT GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGT GGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCG TGATGCATGAGGCTCTGCACAACCACTACACGCAGAAAAGCCTCTCCCTGTCCCCCGGTAAADescription Sequence SEQ ID NO GACGTGGTCATGACCCAGAGCCCACTGTCTCTGCCCGTGACACT GGGCCAGCCAGCCTCTATCTCCTGCAGGTCCAGCCAGTCCCTGG TGTACAGCGATGGCAACACCTATCTGAATTGGTTCCAGCAGAGA CCTGGCCAGAGCCCAAGGCGGCTGATCTACAAGGTGTCTAACAG AGACTCCGGAGTGCCAGATCGCTTCAGCGGCTCTGGCTCCGGAA CCGACTTTACACTGAAGATTTCTCGTGTTGAGGCTGAGGATGTG GGCGTGTACTATTGTATGCAGGGCACCCACTGGCCCCCTACCTT CACATTTGGCCCTGGCACAAAGGTGGACATCAAGCGTACGGTGG33726 LC CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG 75 AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTA TCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCC AATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAG GACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGC AGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAG TGT GAGGTGCAGCTGGTGCAGAGCGGAGCTGAGGTGAAGAAGCCAGG CGAGTCCCTGAAGATCAGCTGCAAGGGCTCCGGCTACAGCTTCA CCTCTTATTGGATTGGTTGGGTTAGACAGATGCCAGGAAAGGGC CTTGAATGGATGGGAACCATCTACCCCGGCGACTCTGATACACG CTATAGTCCTAGTTTCCAAGGTCAGGTTACCATCTCCGCCGACA AGAGCATCTCTACAGCTTTTCTTCAATGGAGTAGCCTGAAGGCC TCTGATACAGCTATGTACTATTGTGCCATCAAGGGCAGGTACCG GACCGCTTTTGACATCTGGGGCCAGGGCACCACAGTGACAGTCT CGAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACT CAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATC ACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAA33733 HC TCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA 76 AGCCGAAGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA AGGACACCCTGATGATCTCCCGGACCCCTGAGGTCACATGCGTG GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC GGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTG CAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCA TCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC CTGCCCCCATCCCGCGAGGAGATGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAA GCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAAAGCCTCTCCCTGTCCCCCGGTAAADescription Sequence SEQ ID NO GACATCGTGATGACCCAGTCCCCACTGTCTCTGTCCGTGACACC AGGACAGCCTGCCAGCATCTCTTGCAAGTCCAGCCAGTCCCTGC TGCACAGCAACGGCTACAATTATCTGGGTTGGTATCTTCAAAAG CCAGGCCAGAGCCCCCAGTTCCTGATCTATCTGGGCTCTAACAG GGCTTCCGGAGTGCCTGACAGGTTCTCCGGCAGCGGCTCTGGAA CCGATTTCACTCTTAAGATTTCTAGGGTTGAGGCCGAGGATGTG GGCGTGTACTATTGTATGCAGGCTCTGCAGACCCCATACACATT33733 LC TGGCCAGGGCACCAAGCTGGAGATCAAGCGTACGGTGGCTGCAC 77 CATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGG GTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGC ACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0171] Table 6 shows SEQ ID NO information for antibodies 33628, 32302, 33726, and 33733, including the SEQ ID NOs of the CDRs according to the IMGT® system (nt: nucleotide; aa: amino acid).Table 6: Anti-IL21R Antibody SEQ ID NOsName VH aa VLaa VHnt VLnt HC aa LC aa HC nt LC nt 33628 1 2 9 10 62 63 70 71 32302 11 12 19 20 64 65 72 73 33726 21 22 29 30 66 67 74 7533733 31 32 39 40 68 69 76 77 Name HCDR1 HCDR2 HCDR3 LCDR1 LCDR2 LCDR333628 3 4 5 6 7 832302 13 14 15 16 17 1833726 23 24 25 26 27 2833733 33 34 35 36 37 38

[0172] Table 7 shows full-length heavy and light chain amino acid sequences with their corresponding SEQ ID NOs for analogues of select anti-IL121 and anti-IL21R antibodies used as comparators in experiments herein. The protein sequences were reverse-translated and codon-optimized for expression in CHO cells. The corresponding DNA sequences were gene synthesized and cloned into expression vectors containing human heavy or light chain constant regions, resulting in expression of full-length antibody chains. CHO cells were transfected with the generated expression plasmids using a standard protein expression system. The corresponding antibody supernatants were purified using standard protein A chromatography.

[0173] The ATR-107 analogue antibody of Table 7 comprises the VH and VL of antibody “AbS” as disclosed in the international patent application published as WO 2009 / 143526 Al, which was otherwise disclosed as antibody “Ab-01” in Vugmeyster et al., 2010, mAbs, 2:3, 335-346. The C2 analogue antibody of Table 7 comprises the VH and VL of antibody C2 as disclosed in Campbell et al., 2021, MABS, Vol. 13, No. 1, el883239.Table 7: Heavy and Light Chain Amino Acid Sequences ofAnti-IL21 and Anti-IL21R Antibody AnaloguesSEQAntibody Chain Sequences ID NO QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYYWGWIRQ PPGKGLEWIGSISHTGNTYYNPPLKSRVTISVDTSKNQFS LKLSSVTAADTAVYYCARGGGISRPEYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAEGAPS HC VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV 45 ATR-107DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYanalogueKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT(anti-IL21R, KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDIgGi-3f SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK format) SLSLSPGK SSELTQDPAVSVALGQTVRITCQGDSLRTYYASWYQQKPG QAPVLVIYGKHKRPSGIPDRFSGSSSGNTASLTITGAQAE DEADYYCMSRSIWGNPHVLFGGGTQLTVLGQPKAAPSVTL LC FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA 46 GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH EGSTVEKTVAPTECS Q VQL VE S GGGVVQ PGRS LRL S CAAS G FT F S S YGMH WVRQ A PGKGLEWVAFIWYDGSDKYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARDGDSSDWYGDYYFGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA HC PEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP 47 NNC0114EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQanalogueDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTL(anti-IL21, PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYIgGi-3f KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA format) LHNHYTQKSLSLSPGK EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK PGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGSWTFGQGTKVEIKRTVAAPSVFIFPPS LC DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 48 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ Antibody Chain Sequences ID NO QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYWMHWVRQA PGQGLEWMGTIDPSDQYTIYSQNFKGRVTMTRDTSTSTVY MELSSLRSEDTAVYYCARYGFAMDYWGQGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF HC LFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDG 49 BOS161721 VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC analogue KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN (anti-IL21, QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD IgGi format) GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK DIQLTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKP GKAVKLLIYYTSRLHSGVPSRFSGSGSGTDYTLTISSLQP EDFATYYCQQGHTLPRTFGGGTKVEIKRTVAAPSVFIFPP LC SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 50 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC Q VQL VE S GGGVVQ PGRS LRL S CAAS GVT F S D Y HMAWVRQ A PGKGLEWVATIIYDAARTYYRDSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCATWQTTGTPGWFAYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAG HC GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN 51 C2 analogue WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG (anti-IL21R, KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE IgGi LALA EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP format) VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK DIQMTQSPSSLSASVGDRVTITCGASQSVSISRFNLMHWY QQKPGKAPKLLIYRASNLASGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQSRESPPTFGQGTKVEIKRTVAAPSVF LC I FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS 52 GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECHC: heavy chainLC: light chainSEQ: SEQ ID NOExample 2: Generation of affinity-matured anti-IL21R antibodies from yeast display selectionsMaterials and Methods

[0174] The affinity maturation of antibody 33628 was performed at Specifica Inc. The strategy involved diverse library designs and multiple rounds of yeast display selections. First, the antibody was reformatted to a single-chain variable fragment (scFv) to enabledisplay on the yeast cell surface. After confirming binding to the target, four individual libraries were designed based on the parent antibody sequence to fully explore the potential at each site and decrease the initial combinatorial diversity. Four separate sub-libraries were created: LCDR1+2, LCDR3, HCDR1+2 and lastly d) HCDR3. The strategy for the library design (LCDR1+2, LCDR3 and HCDR1+2) involved substituting the parental sequence at a specific site with V-germline matching CDRs. The CDR diversity was derived from a proprietary database of natural human CDRs. Furthermore, sequence liabilities such as N-linked glycosylation sites were eliminated from the design. The HCDR3 library was designed by scanning mutagenesis, where each amino acid position was substituted with all other amino acids, excluding cysteine, at up to two positions at the time (single and double scanning mutagenesis).

[0175] The four sub-libraries each went through two rounds of selection against the recombinant antigen, after which the enriched clones were recovered by PCR and assembled into two combinatorial libraries. One library named “Combo” library that included maximum diversity in all 6 CDR’s, and a second library named “Combo HCDR3” that preserved the parent HCDR3 sequence but included diversity in the remaining CDRs. Multiple rounds of yeast display selections were performed on the “Combo” and “Combo HCDR3” libraries using both magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS) selecting for high-affinity clones that competed with ligand binding.

[0176] After the final selection, single yeast colonies were picked, PCR amplified and sequenced by Sanger sequencing. Unique clones were selected for mammalian expression as full-length human IgGl antibodies in the IgG1.3F isotype for further affinity- and functional characterization. Six of these antibodies are included in the patent: 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927.Results

[0177] Table 8 shows the nucleotide sequences encoding the variable domains of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927.Table 8: Variable domain nucleotide sequences of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927Sequence (5' to 3') SEQ ID NO: 33628. CAGCTCCAGCTGCAAGAGTCTGGCCCTGGACTGGTCAAGCCTTCCGAGAC 78 39191 ACTGTCTCTGACCTGCACAGTGTCCGGCGGCTCTATCTCCGGCTCTAATTVH ACTGGGGCTGGATCAGACAGCCTCCTGGCAAAGGATTGGAGTGGTTCGGC TCCATCTCCACCACCGGCAGAACCTACTACAACCCCAGCCTGAAGTCCAG AGTGACCATCTCCGTGGACACCTCCAAGAACCAGTTCTCCCTGAAGCTGT CCTCCGTGACCGCTGCTGATACCGCCGTGTACTACTGCGCCTCCAGAGAG GCTTCTGCTGGCACCGGCTTTGACTATTGGGGCCAGGGAACACTGGTCAC CGTGTCCTCT33628. CAGCTCCAGCTGCAAGAGTCTGGCCCTGGACTGGTCAAGCCTTCCGAGAC 79 39218 ACTGTCTCTGACCTGCACAGTGTCCGGCGGATCTCTGTCTGGCGATTACTVH GGGGCTGGATCAGACAGCCTCCTGGCAAAGGATTGGAGTGGTTCGGCTCC ATCTCCACCTCCGGCAGAACCTACTACAACCCCAGCCTGAAGTCCAGAGT GACCATCTCCGTGGACACCTCCAAGAACCAGTTCTCCCTGAAGCTGTCCT CCGTGACCGCTGCTGATACCGCCGTGTACTACTGCGCCAGAAGAGAGGCT GCTGCCGGCACCGGCTTTGATTATTGGGGACAGGGCACCCTGGTCACCGT GTCCTCT33628. CAGCTCCAGCTGCAAGAGTCTGGCCCTGGACTGGTCAAGCCTTCCGAGAC 80 39219 ACTGTCTCTGACCTGCACAGTGTCCGGCGGCTCCATCTCCTCCAGCTCTTVH ATTACTGGGGCTGGATCAGACAGCCTCCTGGCAAAGGATTGGAGTGGTTC GGCAGCATCTCCACCACCGGCAGAACCTACTACAACCCCAGCCTGAAGTC CAGAGTGACCATCTCCGTGGACACCTCCAAGAACCAGTTCTCCCTGAAGC TGTCCTCCGTGACCGCTGCTGATACCGCCGTGTACTACTGCGCCAGAAGA GAGGCTGCTGCCGGCACCGGCTTTGATTATTGGGGACAGGGCACCCTGGT CACCGTGTCCTCT33628. CAGCTCCAGCTGCAAGAGTCTGGCCCTGGACTGGTCAAGCCTTCCGAGAC 81 39223 ACTGTCTCTGACCTGCACCGTGTCCGGCTACTCCATCTCTTCTGGCGATTVH ACTGGGGCTGGATCAGACAGCCTCCTGGCAAAGGATTGGAGTGGTTCGGC TCCATCTCCACCACCGGCAGAACCTACTACAACCCCAGCCTGAAGTCCAG AGTGACCATCTCCGTGGACACCTCCAAGAACCAGTTCTCCCTGAAGCTGT CCTCCGTGACCGCTGCTGATACCGCCGTGTACTACTGCGCTAGAAGAGAG GCTGCTGCCGGCACCGGCTTTGATTATTGGGGACAGGGCACCCTCGTGAC CGTGTCCTCT33628. CAGCTCCAGCTGCAAGAGTCTGGCCCTGGACTGGTCAAGCCTTCCGAGAC 82 39230 ACTGTCTCTGACCTGCACCGTGTCTGGCGCCTCTATCTCCTCCGGCTCTTVH TTTACTGGGGCTGGATCAGACAGCCTCCTGGCAAAGGATTGGAGTGGTTC GGCTCCATCTCCACCTCCGGCAGAACCTACTACAACCCCAGCCTGAAGTC CAGAGTGACCATCTCCGTGGACACCTCCAAGAACCAGTTCTCCCTGAAGC TGTCCTCCGTGACCGCTGCTGATACCGCCGTGTACTACTGCGCCAGAAGA GAGGCTGCTGCCGGCACCGGCTTTGATTATTGGGGACAGGGCACCCTGGT CACCGTGTCCTCT33628. CAACTACAACTACAAGAAAGTGGTCCAGGTCTCGTGAAGCCTTCCGAGAC 83 40927 ACTGTCCCTGACCTGTACCGTGTCCGGCGGCTCCATCAGCTCTAGCTCCTVH ACTATTGGGGCTGGATCAGACAGCCTCCTGGCAAGGGCCTGGAATGGTTC GGCTCTATCTCTACCACAGGCAGAACCTACTACAACCCCTCTCTGAAATC CAGAGTGACCATCTCCGTGGACACCTCCAAGAACCAGTTTAGCCTGAAGC TGTCTTCTGTGACCGCTGCCGATACCGCCGTGTACTACTGCGCCCGGAGA GAGGCCGCTGCTGGCACCGGCTTCGACTACTGGGGCCAGGGAACCCTGGT CACAGTCTCGAGT33628. GAGATCGTGCTGACACAGACCCCTGCCACACTGTCACTGTCTCCAGGCGA 84 39191 GAGAGCTACCCTGTCCTGTAGAGCCTCTCAGTCTATCGGCACCTTCCTGGVL CCTGGTATCAGCAGAAGCCTGGACAGGCTCCCCGGCTGTTGATCTATGGC GCTACCTCTAGAGCCGCTGGCATCCCTGCTAGATTCTCCGGCTCTGGCTC TGGCACCGACTTTACCCTGACCATCTCCAGCCTGGAACCTGAGGACTTCG CCGTGTACTACTGCCAGCAGCGGTCTAGAACCTTTGGCCAGGGCACCAAG GTGGAAATCAAG33628. GAGATCGTGCTGACACAGACCCCTGCCACACTGTCACTGTCTCCAGGCGA 85 39218 GAGAGCTACCCTGTCCTGTAGAGCCTCTCAGTCCATCGGCTCTTACCTGGVL CCTGGTATCAGCAGAAGCCTGGACAGGCTCCCCGGCTGTTGATCTACGAG GGCTCTATCAGAGCCACAGGCATCCCCGCCAGATTCTCCGGATCTGGCTC TGGCACAGACTTTACCCTGACCATCTCCAGCCTGGAACCTGAGGACTTCG CCGTGTACTACTGCCAGCAGCGGTCTAGAACCTTTGGCCAGGGCACCAAG GTGGAAATCAAG33628. GAGATCGTGCTGACACAGACCCCTGCCACACTGTCACTGTCTCCAGGCGA 86 39219 GAGAGCTACCCTGTCCTGTAGAGCCTCTCAGTCCGTGGCCTCTTTCCTGGVL CCTGGTATCAGCAGAAGCCTGGACAGGCTCCCCGGCTGTTGATCTACGGC GCCTCTAATAGAGCCCCTGGCATCCCTGCCAGATTCTCCGGATCTGGCTC TGGCACCGACTTTACCCTGACCATCTCCAGCCTGGAACCTGAGGACTTCG CCGTGTACTACTGCCAGCAGCGGTCTAGAACCTTTGGCCAGGGCACCAAG GTGGAAATCAAG33628. GAGATCGTGCTGACACAGACCCCTGCCACACTGTCACTGTCTCCAGGCGA 87 39223 GAGAGCTACCCTGTCCTGTAGAGCCTCTCAGTCCGTGTCCAGATTCCTGGVL CCTGGTATCAGCAGAAGCCTGGACAGGCTCCCCGGCTGTTGATCTACGGC GCTTCTACAAGAGCCCCTGGCATCCCTGCCAGATTTTCCGGCTCTGGCTC TGGCACCGACTTTACCCTGACCATCTCCAGCCTGGAACCTGAGGACTTCG CCGTGTACTACTGCCAGCAGCGGTCTAGAACCTTTGGCCAGGGCACCAAG GTGGAAATCAAG33628. GAGATCGTGCTGACACAGACCCCTGCCACACTGTCACTGTCTCCAGGCGA 88 39230 GAGAGCTACCCTGTCCTGTAGAGCCAGCCACTCCGTGTCTAGCTTTCTGGVL CCTGGTATCAGCAGAAGCCCGGCCAGGCTCCTAGACTGTTGATCTACGGC GCCACCAATAGAGCCCCTGGCATCCCTGCTAGATTCTCCGGCTCTGGCTC TGGCACCGACTTTACCCTGACCATCTCCAGCCTGGAACCTGAGGACTTCG CCGTGTACTACTGCCAGCAGCGGTCTAGAACCTTTGGCCAGGGCACCAAG GTGGAAATCAAG33628. GAAATCGTGCTAACTCAAACTCCAGCAACTCTCTCTCTGTCTCCTGGCGA 89 40927 GAGAGCTACACTGAGCTGTAGAGCCTCTCAGTCCGTGTCCAGCTTTCTGGVL CCTGGTACCAGCAAAAACCAGGACAGGCTCCTAGACTGCTGATCTACGAC GCCTCCAACCGGGCTACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCTC TGGCACCGACTTCACCCTGACCATCTCCTCCCTGGAACCCGAGGATTTCG CCGTGTACTACTGCCAGCAGCGGTCTCGGACCTTCGGCCAGGGCACCAAG GTGGAGATCAAG

[0178] Table 9 shows the amino acid sequences of the variable domains of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927. CDRs are in bold / underlined and defined according to the IMGT® numbering scheme.Table 9: Variable domain amino acid sequences of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927Sequence (N-terminal to C-terminal) SEQ ID NO: 33628.39191 QLQLQESGPGLVKPSETLSLTCTVSGGSISGSNYWGWIRQPP 90 VH GKGLEWFGSISTTGRTYYNPSLKSRVTISVDTSKNQFSLKLS SVTAADTAVYYCASREASAGTGFDYWGQGTLVTVS S33628.39218 QLQLQESGPGLVKPSETLSLTCTVSGGSLSGDYWGWIRQPPG 96 VH KGLEWFGSISTSGRTYYNPSLKSRVTISVDTSKNQFSLKLSS VTAADTAVYYCARREAAAGTGFDYWGQGTLVTVS S33628.39219 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQP 101 VH PGKGLEWFGSISTTGRTYYNPSLKSRVTISVDTSKNQFSLKL S SVTAADTAVYYCARREAAAGTGFDYWGQGTLVTVS S 33628.39223 QLQLQESGPGLVKPSETLSLTCTVSGYSISSGDYWGWIRQPP 104 VH GKGLEWFGSISTTGRTYYNPSLKSRVTISVDTSKNQFSLKLS SVTAADTAVYYCARREAAAGTGFDYWGQGTLVTVS S33628.39230 QLQLQESGPGLVKPSETLSLTCTVSGASISSGSFYWGWIRQP 108 VH PGKGLEWFGSISTSGRTYYNPSLKSRVTISVDTSKNQFSLKL S SVTAADTAVYYCARREAAAGTGFDYWGQGTLVTVS S 33628.40927 QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQP 112 VH PGKGLEWFGSISTTGRTYYNPSLKSRVTISVDTSKNQFSLKL S SVTAADTAVYYCARREAAAGTGFDYWGQGTLVTVS S 33628.39191 EIVLTQTPATLSLSPGERATLSCRASQSIGTFLAWYQQKPGQ 91 VL APRLLIYGATSRAAGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK33628.39218 EIVLTQTPATLSLSPGERATLSCRASQSIGSYLAWYQQKPGQ 97 VL APRLLIYEGSIRATGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK33628.39219 EIVLTQTPATLSLSPGERATLSCRASQSVASFLAWYQQKPGQ 102 VL APRLLIYGASNRAPGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK33628.39223 EIVLTQTPATLSLSPGERATLSCRASQSVSRFLAWYQQKPGQ 105 VL APRLLIYGASTRAPGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK33628.39230 EIVLTQTPATLSLSPGERATLSCRASHSVSSFLAWYQQKPGQ 109 VL APRLLIYGATNRAPGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK33628.40927 EIVLTQTPATLSLSPGERATLSCRASQSVSSFLAWYQQKPGQ 113 VL APRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFA VYYCQQRSRTFGQGTKVEIK

[0179] The affinity matured antibodies were produced with the same constant domains (IgG1.3F isotype and kappa light chain) as described above.

[0180] Table 10 shows the amino acid sequences of the CDRs of variable domains of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927.Table 10: CDR amino acid sequences defined according to the IMGT numbering scheme of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927Name Sequence (N-terminal to C-terminal) (and SEQ ID NOs:)H-CDR1 H-CDR2 H-CDR3 L-CDR1 L-CDR2 L-CDR3 33628. GGS ISGSNY ISTTGRT ASREASAGTGFDY QS IGTF GAT QQRSRT 39191 ( 92 ) ( 93 ) ( 94 ) ( 95 ) ( 114 ) ( 8 ) 33628. GGSLSGDY ISTSGRT ARREAAAGTGFDY QS IGSY EGS QQRSRT 39218 ( 98 ) ( 99 ) ( 5 ) ( 100 ) ( 115 ) ( 8 ) 33628. GGS ISSSSYY ISTTGRT ARREAAAGTGFDY QSVASF GAS QQRSRT 39219 ( 3 ) ( 93 ) ( 5 ) ( 103 ) ( 116 ) ( 8 ) 33628. GYS ISSGDY ISTTGRT ARREAAAGTGFDY QSVSRF GAS QQRSRT 39223 ( 106 ) ( 93 ) ( 5 ) ( 107 ) ( 116 ) ( 8 ) 33628. GAS ISSGSFY ISTSGRT ARREAAAGTGFDY HSVSSF GAT QQRSRT 39230 ( 110 ) ( 93 ) ( 5 ) ( 111 ) ( 114 ) ( 8 ) 33628. GGS ISSSSYY ISTTGRT ARREAAAGTGFDY QSVSSF DAS QQRSRT 40927 ( 3 ) ( 93 ) ( 5 ) ( 6 ) ( 7 ) ( 8 )

[0181] The sequences of HC and LC of antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230 and 33628.40927, with IgGl-3f CH and Kappa CL, respectively, are shown in sequences:SEQ ID NO: 117 and SEQ ID NO: 118 (33628.39191);SEQ ID NO: 119 and SEQ ID NO: 120 (33628.39218);SEQ ID NO: 121 and SEQ ID NO: 122 (33628.39219);SEQ ID NO: 123 and SEQ ID NO: 124 (33628.39223);SEQ ID NO: 125 and SEQ ID NO: 126 (33628.39230); andSEQ ID NO: 127 and SEQ ID NO: 128 (33628.40927).Example 3: Measurement of Antibody Binding Kinetics Towards Human and Cynomolgus IL21R ECD

[0182] This example describes in vitro binding of anti-IL21R antibodies to recombinant human and cynomolgus IL21R extracellular domains (ECDs) as measured by surface plasmon resonance (SPR).Materials and Methods

[0183] Anti-IL21R antibodies 33628, 33733, 32302, and 33726 were tested for binding to recombinant human and cynomolgus IL21R (C-terminally His-tagged from Sino Biological) by Surface Plasmon Resonance (SPR) using Carterra® LSA™ or Carterra® LSA™ XT. An HC30M (Carterra®) chip was functionalized by goat anti-human Ig Fc (Southern Biotech) using amine-coupling. The chip was activated by freshly prepared 0.4 M EDC, 0.1 M sulfo-NHS, and 0.1 M MES, pH 5.5 (1 : 1 : 1 v / v / v) for 5 min, coupled with 75 pg / mL anti-human Ig Fc in 10 mM sodium acetate, pH 4.5, for 10 min, and excess reactive esters were quenched for 3 min by injection of 1 M ethanolamine, pH 8.5. The instrument was primed in running buffer (PBS pH 7.4, 0.01% Tween-20, 0.5 mg / mL BSA). After priming and washing, antibodies were captured onto individual spots of the chip for 12 minutes at 0.016 - 0.5 pg / mL as singlicates, duplicates or quadruplicates in 1-2 individual experiments. Kinetic analysis was performed by applying kinetic titration series of each antigen as increasing concentrations. Antigen association was performed for 10 minutes, and antigen dissociation was recorded for 10-20 minutes. After each cycle, the surface was regenerated by 0.425% H3PO4 for 2x20 s and washed for 5 min in running buffer. Binding responses were processed and analyzed using Carterra’s KIT software tool. Processed data were fitted to a simple Langmuir 1 : 1 binding model for calculation of the on-rate (konor ka), off-rate (koff or kd) and affinity (KD) constants.Results

[0184] The binding kinetics of anti-IL21R antibodies are shown in Table 11. Each antibody 33628, 33733, 32302, and 33726, was measured in 1-4 technical replicates in a total of 1-2 independent experiments. Each antibody 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, and 33628.40927, was measured in 1-4 technical replicates in a total of 1-4 independent experiments. The ATR-107 analogue was included as a comparator.The average values together with the standard deviation (SD) for each are presented in the table.Table 11: Antibody Binding Kinetics Towards Human and Cynomolgus IL21R ECDkon (x 105M Mean koff (x Mean log(KD) KD Antibody Antigen1s’1) ± SD 104s -1) ± SD. (M) ± SD (nM) Human 11.1 ± 0.6 3.52 ± 0.03 -9.50 ± 0.03 0.32 33628Cyno 17.1 ± 0.7 14.0 ± 0.3 -9.09 ± 0.02 0.82 Human 4.5 ± 0.2 2.9 ± 0.4 -9.19 ± 0.04 0.64 33733Cyno 4.9 ± 0.1 7.3 ± 0.1 -8.83 ± 0.01 1.5 Human 9 ± 2 14 ± 3 -8.82 ± 0.04 1.5 32302Cyno 8 ± 4 23 ± 6 -8.5 ± 0.1 2.9 Human 10.8 ± 0.5 5 ± 1 -9.3 ± 0.1 0.47 33726 Not NotCyno Not determined >10 determined determinedHuman 11.1 ± 0.6 3.52 ± 0.03 -9.50 ± 0.03 0.32 33628Cyno 17.1 ± 0.7 14.0 ± 0.3 -9.09 ± 0.02 0.82 Human 19 ± 5 4 ± 2 -9.7 ± 0.3 0.20 33628.39191Cyno 18 ± 3 8 ± 3 -9.4 ± 0.2 0.40 Human 15 ± 3 3 ± 2 -9.7 ± 0.2 0.21 33628.39218Cyno 18 ± 3 4.8 ± 0.7 -9.6 ± 0.1 0.27 Human 23 ± 11 2 ± 1 -10.0 ± 0.2 0.10 33628.39219Cyno 24 ± 8 5 ± 1 -9.7 ± 0.1 0.19 Human 24 ± 17 3 ± 1 -9.8 ± 0.3 0.15 33628.39223Cyno 20 ± 8 5 ± 2 -9.6 ± 0.2 0.25 Human 23 ± 14 6 ± 3 -9.6 ± 0.1 0.25 33628.39230Cyno 19 ± 11 6 ± 4 -9.6 ± 0.2 0.28 Human 17 ± 7 2 ± 1 -9.9 ± 0.3 0.12 33628.40927Cyno 16 6 -9.5 0.30 ATR-107 Human 5 ± 1 1.2 ± 0.8 -9.6 ± 0.3 0.24analogue Cyno 3.3 ± 0.5 2 ± 1 -9.3 ± 0.2 0.49

[0185] The antibodies exhibit high affinities in the sub- to low-nanomolar range for binding to the extracellular domain of recombinant human IL21R and demonstrate similar affinities for cynomolgus IL21R, except for 33726.Example 4: Direct Binding of Antibodies to IL21R-Transfected CHO-S cells

[0186] This example describes in vitro binding of anti-IL21R antibodies (i) 33628, 33733, 32302, and 33726 to CHO-S cells transiently expressing human, cynomolgus or mouse IL21R, (ii) 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, and 33628.40927 to CHO-S cells transiently expressing human, or cynomolgus IL21R. The ATR-107 analogue was included as a comparator.Materials and Methods

[0187] The anti-IL21R antibodies were incubated with hamster CHO-S cell line transiently expressing human, cynomolgus or mouse IL21R for 30 minutes at 4°C. Mock-transfected cells were included as negative controls. Cells were previously encoded with different intensities of violet dye (Sartorius) which made it possible to seed all the cell populations in the same well and distinguish them. After a washing step, cells were incubated for an additional 30 minutes at 4°C in the dark with AF647-conjugated secondary anti-human IgG (H+L) antibody (Thermo). After a final washing step, antibody binding was detected using the high-throughput flow cytometer iQue Screener PLUS (Sartorius) measuring the GeoMean of AF647 signal in each well. Antibodies were tested for binding to the transfected cells in a 12-point titration curve for each antibody, and every concentration was assayed in triplicate.Results

[0188] Efficacy and ECso values were calculated using GraphPad Prism 10 software and are shown in Tables 12 and 13. Data in the tables are shown as means of triplicates.Table 12. Efficacy and ECso Values for Antibody Binding toIL21R-Transfected CHO-S CellsEC50(nM) Efficacy (GeoMean AF647) Antibody Human Cynomolgus Mouse Human Cynomolgus Mouse Name IL21R IL21R IL21R IL21R IL21R IL21R 33628 0.6528 1.229 4.823 637515 675927 87827 33733 4.523 5.866 12.4 761634 889696 7442 32302 0.3447 0.4099 3.632 581360 630731 6424 33726 0.5392 4.319 8.591 806489 64000 6261 ATR-1070.7858 0.8946 0.9542 576234 568864 756600analogueTable 13. Efficacy and ECso Values for Antibody Binding toIL21R-Transfected CHO-S CellsEC50 (nM) Efficacy (GeoMean AF647) Cynomolgus Cynomolgus Antibody Name Human IL21R Human IL21RIL21R IL21R 33628.39191 2.320 2.403 1011098 1187366 33628.39218 2.214 2.587 896279 951669 33628.39219 2.433 2.649 905436 980978 33628.39223 4.689 4.978 918347 1047160 33628.39230 3.768 3.451 784026 784436 33628.40927 1.720 1.644 557331 635097ATR-107 analogue 3.100 3.297 464836 480156

[0189] The binding curves of the antibodies to human, cynomolgus, or mouse IL21R expressed on the surface of CHO-S cells, as well as mock-transfected cells, are shown in FIG. 1

[0190] Antibodies 33733, 32302, and the ATR-107 analogue bound to human IL21R and cynomolgus IL21R with similar potency and efficacy, while antibody 33733 showed lower potency. Antibody 33726 bound to human IL21R with better potency and efficacy compared to cynomolgus IL21R.

[0191] Antibody 33628 bound to human IL21R with similar efficacy but better potency compared to cynomolgus IL21R.

[0192] Antibody 33628 bound to mouse IL21R with significantly reduced efficacy compared to human IL21R, while antibodies 33733, 32302 and 33726 did not display binding to mouse IL21R. The ATR-107 analogue bound to mouse IL21R with similar potency and efficacy compared to human IL21R.

[0193] Antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, and 33628.40927 bound to human IL21R and cynomolgus IL21R with similar potency and efficacy.Example 5: Antibody Blocking of Human IL21 Ligand (IL21L) Binding to Human or Cynomolgus IL21R-Transfected CHO-S cells

[0194] This example describes blocking of the binding of IL21R ligand human IL21 (IL21L) to human or cynomolgus IL21 receptor (IL21R) transiently expressed on the surface of CHO-S cells by anti-IL21R antibodies.Materials and Methods

[0195] Hamster CHO-S cells expressing human or cynomolgus IL21R, or mock-transfected, were encoded with different intensities of violet encoder dye (Sartorius) to allow detection of each population seeded in the same well. After seeding the cells, the anti-IL21R antibodies were serially diluted from 200 nM to 3 pM in a 3 -fold serial dilution and subsequently added to the cells in each well and incubated for 30 minutes at 4°C. After a washing step, 200 ng / mL recombinant human, Fc-tagged, AF647-labelled IL21 was added to the wells and incubated for a further 30 minutes at 4°C. After a final washing step, binding of IL21-Fc to IL21R expressed on CHO-S cells was detected using the high-throughput flow cytometer iQue3 (Sartorius) measuring the GeoMean of AF647 signal in each well. A 12-point curve was generated for each antibody and every concentration was analyzed in triplicate.Results

[0196] Antibody 33628 efficiently blocked binding of IL21-Fc to human and cynomolgus IL21R expressed on the surface of CHO-S cells with better potency and efficacy compared to the other antibodies tested as shown in FIG. 2. ATR-107 analogue antibody had slightly reduced efficacy for blocking of IL21-Fc binding to cynomolgus IL21R, although comparable in potency to antibody 33628.

[0197] Antibody 33726 only partially blocked IL21-Fc binding to cynomolgus IL21R.

[0198] Antibodies 33733 and 32302 blocked IL21-Fc ligand binding to both human and cynomolgus IL21R with slightly lower efficacy and potency compared to antibody 33628.

[0199] Antibodies 33628.39218, 33628.39219, 33628.39223, 33628.39230, and 33628.40927 efficiently blocked binding of IL21-Fc to human and cynomolgus IL21R expressed on the surface of CHO-S cells, and with improved potency compared to ATR-107 analogue antibody.

[0200] Antibody 33628.39191 blocked binding of IL21-Fc to human and cynomolgus IL21R expressed on the surface of CHO-S cells with similar potency and efficacy, but was less potent than other antibodies.

[0201] Table 14 and Table 15 show efficacy and IC50 values for blocking of IL21L binding to human or cynomolgus IL21R transiently expressed on CHO-S cells by the anti-IL21R antibodies. Data are shown as means of triplicates.Table 14. Efficacy and ICso Values for Blocking of IL21L Binding to IL21R-Transfected CHO-S cellsIC50(nM) IL21 Residual binding (%) Human Cynomolgus Human Cynomolgus Antibody IL21R IL21R IL21R IL21R 33628 1.40 1.62 4.6 5.6 33733 6.46 6.97 13.0 11.8 32302 2.26 2.76 11.5 12.1 33726 6.07 61.78 5.7 53.4ATR-107 analogue 1.10 1.54 13.1 15.1Table 15. Efficacy and ICso Values for Blocking of IL21L Binding to IL21R-Transfected CHO-S cellsICso (nM) IL21 Residual binding (%) Human Cynomolgus Human Cynomolgus Antibody IL21R IL21R IL21R IL21R 33628.39191 2.95 3.25 19.5 21.1 33628.39219 0.66 0.77 16.3 16.3 33628.39223 0.82 0.90 14.9 16.1 33628.39230 0.57 0.62 15.4 16.6 33628.39218 0.46 0.60 19.2 18.1 33628.40927 0.61 0.69 18.2 17.8ATR-107 analogue 1.42 1.72 15.9 14.6Example 6: Antagonistic Activity of Anti-IL21R Antibodies Assessed by a Cell Line STAT3 Luciferase Reporter Assay and a Healthy Donor B Cell Viability Assay

[0202] This example describes in vitro functional evaluation of anti-IL21R antibodies 33628, 33733, 32302, and 33726 as well as affinity-matured variants of 33628 (33628.39191, 33628.39218, 33628.39219, 33628.39223, 33628.39230, 33628.40927) with the purpose of examining antibody antagonistic functionality in comparison to three reference antibody analogues, BOS16172, NNC0114, and ATR-107.

[0203] The antibodies were first evaluated for their ability to reduce IL21 -induced STAT3-mediated signaling in a KMS11 cell line endogenously expressing IL21R and transduced with a ST AT3 -responsive luciferase reporter construct purchased from G&P Biosciences (USA).

[0204] Second, the antibodies were tested for their ability to inhibit proliferation induced by IL21 signaling of isolated primary B cells from healthy human donors, as measured by number of viable B cells after a four-day incubation period.Materials and MethodsKMS11ST AT 3 -luciferase reporter assays

[0205] IL21R+KMS11 cells harboring a STAT3-Luficerase reporter construct were seeded in cell culture medium in 384 well flat bottom plates at 4000 cells / well and incubated for 24 hrs at 37°C. Antibodies and IL21 were added, and plates incubated for 20 hrs. Bio-Glo™ luciferase reagent (Promega, USA) was introduced, and luminescence read in a plate reader after five minutes of incubation.B cell viability assays

[0206] CD19+B cells were isolated from healthy human donor peripheral blood mononuclear cells (PBMCs) and seeded in cell culture medium in 384 well flat bottom plates at 2000 cells / well. The antibodies, 50 nM CD40L, and IL21 were added, and the plates were incubated for 4 days. CellTiter-Glo® reagent (Promega, USA) was added to assess viable B cell number by ATP-driven luminescence, as measured by a luminometer.Results

[0207] The signaling of the STAT3 reporter cells after treatment with the anti-IL21R (or anti-IL21) antibodies is shown in FIG. 3A as a dose-response titration of antibodies up to 166.7 nM against a constant level of IL21 (1 ng / mL). All antibodies displayed antagonist effect, countering the STAT3 Luciferase signaling. However, only two antibodies, 33628 and BOS 161721, reached a full signal abrogation at the highest antibody concentrations with values similar to background (no IL21 added). 33628 displayed an apparent better potency than the BOS161721 reference. In FIG. 3B, 33628 is titrated against affinity matured variants and the reference ATR-107 analogue, indicating improvement in the potency of inhibition of matured variants versus the parental 33628.

[0208] In FIG. 4, 33628, 33733, 32302, and 33726 antibody concentration was held constant at 16.7 nM, while IL21 was titrated up to a level of 400 nM. Again, 33628 and BOS161721 displayed the best apparent potencies, with 33628 performing best.

[0209] The ability of the antagonist antibodies 33628, 33733, 32302, and 33726 to inhibit B cell proliferation induced by 50 ng / mL IL21 is shown in FIG. 5 as a dose-response titration of antibodies up to 166.7 nM. All antibodies displayed antagonist effect, and abrogated proliferation down to the background level (no IL21) at the highest antibody concentrations. However, 33628 clearly displayed the highest apparent potency, while the BOS161721 reference showed the lowest. In FIG. 6, the antibody concentration was held constant at 16.7nM, while IL21 was titrated up to a level of 400 nM. Again, 33628 clearly displayed the highest apparent potency, while the BOS 161721 reference showed the lowest.Example 7: Inhibition of Phospho-STAT Signaling in Primary B Cells

[0210] This example investigates the ability of antibody 33628, affinity maturation antibody 33628.39218 and an ATR-107 analogue to inhibit IL21-induced phospho-STAT 1, STAT3 and STAT5 signaling in primary B cells from two donorsMaterials and Methods

[0211] CD19+B cells were purified from two donors using Miltenyi MACS® system. B-cells were incubated overnight with 50 nM CD40L, washed in PBS and rested 1 hour in media with 1% serum. B cells were pre-incubated with antibodies for 1 hour before stimulation with IL21 for 30 min. After stimulation, B cells were lysed with ice-cold RIPA buffer containing protease and phosphatase inhibitor cocktail.

[0212] Lysates were analyzed using the Sally Sue Simple Western system with antibodies against pan-Actin, p-STATl, p-STAT3 and p-STAT5, all from Cell Signaling Technologies. p-STATs were quantified as area under the curve, normalized to pan-Actin.Results

[0213] As shown in FIG. 7, antibody 33628, 33628.39218 and the ATR-107 analogue both inhibited p-STATl, p-STAT3 and p-STAT5 signaling completely in primary B cells from two donors at both concentrations tested (66.6 nM and 330 nM).Example 8: Functional Activity of Antibody 33628 in a Plasma Cell Differentiation Assay

[0214] This example describes in vitro functional evaluation of anti-IL21R antibody 33628, and affinity maturation antibody 33628.39218, to demonstrate dose-dependent antagonistic activity. The antibody was evaluated for its ability to block IgG-, IgA- and IgE-secreting plasma cell differentiation of B cells in PBMCs from healthy donors. The isotype control, IgGi.3F, was included as a negative control.Materials and MethodsPlasma cell differentiation assayIgG- and IgA-secreting plasma cells:

[0215] PBMCs were isolated from healthy donor blood and incubated with CD40L and IL21 as well as 25 pg / mL of the indicated antibodies. After 4 days of culture, thedifferentiation of plasma cells was measured using FluoroSpot. In brief, PVDF filter 96-well plates were coated with anti-IgG or -IgA monoclonal antibodies (mAbs) and 5xl03cells were transferred to wells and incubated overnight. The next day, the plates were developed by adding fluorophore-conjugated detection mAbs to create fluorescent spots on the bottom of the plates (each representing an IgG- or IgA- secreting plasma cell). Each concentration was assayed in either duplicate or triplicate.IgE-secreting plasma cells:

[0216] PBMCs were isolated from healthy donor blood and incubated with CD40L, IL21, IL-4 and a 5-fold titration of the indicated antibodies starting from 50 pg / mL. After 5 days of culture, the differentiation of plasma cells was measured using enzyme-linked immunospot (ELISPOT). In brief, PVDF filter 96-well plates were coated with anti-IgE mAbs and 5xl05cells were transferred to wells and incubated overnight. The next day, the plates were developed by adding biotinylated anti-IgE mAbs and streptavidin-HRP to generate dark spots on the bottom of the plates (each representing an IgE-secreting plasma cell). Each concentration was assayed in duplicate.Results

[0217] The blocking of plasma cell differentiation after treatment with antibody 33628 and 33628.39218 is shown in FIG. 8. 33628 and 33628.39218 blocked differentiation of IgG-, IgA- and IgE-secreting plasma cells. Inhibition of IgE-secreting plasma cells was shown to be dose dependent.Example 9: Functional Activity of Antibody 33628 in the Restoration of iTreg Differentiation Inhibited by the IL21 Pathway

[0218] This example describes in vitro functional evaluation of antibody 33628 with the purpose of demonstrating a dose-dependent activity. The antibody was evaluated for its ability to restore iTreg differentiation inhibited by the IL21 pathway. BOS 161720 analogue and NNC0114 analogue were included for comparison.Materials and Methods

[0219] Human PBMCs were freshly isolated from anonymized healthy donor buffy coats provided from the French Blood Establishment (EFS). CD4+naive T cells were purified using a commercially available isolation kit according to the manufacturer’s instructions (Miltenyi Biotec) and stimulated with plate-coated anti-CD3 antibody (5 pg / mL, clone OKT3) and soluble anti-CD28 antibody (1 pg / mL, clone CD28.2) in X-VIV015 medium(Lonza) supplemented with rh-IL-2 (R&D Systems) at 50 U / mL, rh-TGF-P (Peprotec) at 5 ng / mL and with or without rh-IL21 at 100 ng / mL (R&D Systems). Anti-IL21R antagonist antibodies (33628 or the BOS161720 or NNC0114 analogue) at different concentrations (from 6.67E-3 nM to 200 nM) or the isotype control (IgGi.3F at 200nM) were then added to the cell culture. After 6 days of incubation at 37°C, cells were harvested and stained with anti-CD4 (BD Biosciences), anti-CD25 (Beckman Coulter) and anti-CD3 (Biolegend) antibodies, fixed and permeabilized (eBioscience) and stained with anti-FoxP3 antibody (Biolegend).

[0220] Flow cytometry analysis was performed using FlowJo software. Graphs and IC50 calculation were performed on GraphPad Prism software.Results

[0221] The ability of anti-IL21R antibodies to restore iTreg differentiation inhibited by the IL21 pathway is shown in FIG. 9. Antibody 33628 was able to restore iTreg differentiation in a dose dependent manner until reaching a plateau at the highest antibody concentrations, at a level comparable to the condition without IL21. Calculated EC50 showed a better potency for antibody 33628 (0.87 nM) as compared to the BOS161720 analogue (1.56 nM) and NNC0114 analogue (1.46 nM). As expected, the isotype control (IgGi-3f) showed no effect on iTreg restoration.Example 10: Assessment of ADCC (PBMC Cell-Mediated Killing) and FcGR Signaling Activity of Anti-IL21R Antibodies Using the IL21R-Positive RAJI Cell Line

[0222] This example describes in vitro functional evaluation of antibody 33628 in the Fc-effector function attenuated format IgG1.3f with the purpose of examining antibodydependent cellular cytotoxicity (ADCC).

[0223] The antibodies were tested for the ability to elicit PBMC-mediated ADCC. For these assays, RAJI B cell cancer cells with endogenous expression of IL21R (Parrish-Novak et al., J Leukoc Biol. (2002) 72(5):856-63) were used as target cells. An ATR107 analogue and an internal anti-IL21R antibody (32355) in the IgGi Fc wild-type (IgGiwt) format were included for comparison and as positive controls to demonstrate an assay window. An IgGi Fc wild-type (IgGiwt) antibody targeting an irrelevant antigen was used as a negative control.Materials and Methods

[0224] RAJI IL21R+target cells were labeled with calcein for 60 minutes. PBMCs were isolated from healthy human donors and added to empty wells together with antibodies in aclear bottom 384 well plate. Calcein loaded cells were added to wells at a 1 :20 (target: effector) ratio and plates incubated for 90 minutes. Calcein levels in supernatants were measured in a fluorescence plate reader. Specific lysis was calculated by subtracting spontaneous lysis (calcein-loaded RAJI cells only, no PBMCs present) and normalizing to maximum lysis (Triton X-100 lysis of calcein-loaded RAJI cells).Results

[0225] ADCC activity is exemplified in FIG. 10 using a representative PBMC donor sample from a cohort of eight healthy donors. Killing activity was observed with the ATR107 analogue and with the internal anti-IL21R antibody 32355, both in the IgGiwt format. Antibody 33628 in the IgG1.3f format induced no additional killing above the background levels observed with a negative control IgGiwt antibody.Example 11: Polyreactivity of Anti-IL21R AntibodiesMaterials and Methods

[0226] 384-well ELISA plates (NUNC™ MaxiSorp™) were coated overnight at 4°C with DNA (10 mg / mL) (Sigma- Aldrich, DI 626) and insulin (5 mg / mL) (Sigma- Aldrich, I9278-5mL) in PBS pH 7.5. An ELISA assay, adapted from assays described in Avery et al., Mabs (2018) 10(2):244-55, was carried out on an Agilent Velocity 11 Bravo liquid handling robot. Wells were washed with water, blocked with polyreactivity ELISA Buffer (PEB; PBS containing 0.05% Tween-20, 1 mM EDTA) for 1 hour at room temperature, and rinsed three times with water. Monoclonal antibodies (mAbs) were diluted to 2 and 10 pg / mL in PBS and added in triplicate to the wells and incubated for 1 hour at room temperature. Plates were washed three times with water, and the secondary reagent 10 ng / mL goat anti -human IgG (Fc specific) conjugated to horseradish peroxidase (Jackson ImmunoResearch, 109-035-008) was added to each well. Plates were incubated for 1 hour at room temperature, washed three times with water, blocked for 5 minutes with the polyreactivity ELISA buffer, and washed again three times with water. Finally, the color reaction was developed with TMB substrate (ECO-TEK Kementec, 4395) added to each well. Reactions were stopped after approximately 7 minutes by adding 0.2 M sulfuric acid to each well, and absorbance was read at 450 nm. DNA- and insulin-assay scores were calculated as the ratio of the ELISA signal of the antibody at 10 mg / mL to the signal of a well containing buffer instead of the primary antibody.Results

[0227] Antibody 33628 is not shown to be polyreactive in the DNA and insulin ELISA assays shown in FIG. 11 A, as 33628 scored lower than the reference ATR-107 and C2 analogues, which are known to be polyreactive anti-IL21R mAbs. Antibodies 32302, 33726 and 33733 also scored lower in the polyreactivity ELISA assays than the reference analogues.

[0228] As shown in FIG. 11B, three of the affinity matured antibodies of 33628 (33628.39191, 33628.39218 and 33628.219) were shown to score lower than the reference ATR-107 and C2 analogues, both in the polyreactivity DNA ELISA and the polyreactivity heparin ELISA. Only one affinity matured antibodies got marked up for having similar score than the reference ATR-107 and C2 analogues in polyreactivity heparin ELISA (33628.40927 EL-1).

[0229] The polyreactivity ELISA was used to discontinue antibodies which had a similar assay score as the C2 analogue or higher to minimize the likelihood of advancing mAbs with poor developability to in vivo studies.Example 12: In Vivo Suppression of Graft-Versus-Host Disease (GvHD)

[0230] This example demonstrates in vivo efficacy of antibody 33628 in limiting GvHD.Materials and Methods

[0231] Human PBMCs freshly isolated from healthy donors were injected into immunodeficient NRG (non-obese diabetic Rag2Tml-I12rgTml) mice 24 hours after 1.5 Gy full-body irradiation. Dosing with antibody 33628 or vehicle started after PBMC transplantation at 20 mg / kg, twice per week. Mice were weighed thrice weekly and monitored daily for any distress. Symptoms of GvHD (i.e., weight loss, anemia, reduced activity, hair loss, posture, bristling fur) were scored blinded. Animals that lost 20% of their initial body weight were sacrificed and scored as 8. Animals reaching a global GvHD score of 6 were also sacrificed (FIG. 12). Flow cytometric analysis was performed to detect the presence of human cells in dissected spleens (FIG. 13), using anti-huCD45-BV805, anti-CD3-BUV496, anti-CD4-BUV395, anti-CD8-BV605, anti-CD25-PECy5, and anti-FoxP3-FITC antibodies. LIVE / DEAD™ Fixable yellow dead cell stain was used for live / dead cell discrimination. Cells were analyzed using a BD FACSymphony™ A3 cell analyzer and the FACSDiva™ software, and data analyses were performed using FlowJo version 10.9.1 and GraphPad Prism version 10.3.1 (GraphPad Software, Inc.).

[0232] Statistical differences between groups were analyzed in GraphPad Prism 10.1.2. Measurements over time were tested by two-way ANOVA for repeated measurements.Kaplan-Meier survival analysis is based on Mantel-Cox Log-rank tests. For statistical differences in flow cytometric analyses, the non-parametric Mann-Whitney test was used. Data are presented as mean ± standard error of the mean (S.E.M.) or as individual observations and median.Results

[0233] As shown in FIG. 12, antibody 33628 dosed twice weekly at 20 mg / kg efficiently inhibited development of GvHD in PBMC-transplanted NRG mice, as demonstrated by sustained weight (Panel A), lower GvHD score (Panel B), and lower mortality (Panel C), compared to vehicle-treated mice.

[0234] Flow cytometric analysis demonstrated significantly reduced levels of human cell engraftment (hCD45+) in 33628-treated mice compared to vehicle-treated mice, indicating that blocking IL21Rby antibody 33628 confers a proliferative disadvantage to transplanted human cells (FIG. 13, Panel A). Furthermore, this effect was associated with a decrease in CD8+cytotoxic T cells as well as an increase in CD4+T cells, although the difference was not statistically significant (FIG. 13, Panels B and D). Strikingly, mice treated with antibody 33628 showed a significant increase in CD25+FoxP3+regulatory T cells (FIG. 13, Panel C).Example 13: Single Dose PK of Antibody 33628 in hFcRn Mice.

[0235] This example determines the single dose PK of antibody 33628, and affinity matured antibodies 33628.39191, 33628.39218, 33628.39219, 33628.39223, 336287.39320, 33628.40927, administered intravenously to hFcRn transgenic mice.Materials and Methods

[0236] In a first experiment, female hFcRn transgenic mice (n=32, Biocytogen, China) received 10 mg / kg of antibody 33628, 33733, 32302, or 33726 intravenously (IV). In a second experiment, female hFcRn transgenic mice (n=40, Biocytogen, China) received 10 mg / kg via intravenous (IV) routes of seven different antibodies (33628.39191, 33628.39218, 33628.39219, 33628.39223, 336287.39320, 33628.40927 and ATR-107 analogue). Plasma samples were collected at specific time points post-dose and analyzed using an automated affinity flow-through assay on the GyroLab xP platform. Biotinylated capture reagent (human IL21R) was bound to streptavidin-coated beads which were pre-packed in microstructure columns of specially designed compact discs. Plasma samples wereautomatically transferred to the columns and bound IL21R antibodies were detected using Alexa Fluor® labeled antibody (goat anti-human IgG antibody). Standards, quality controls (QCs), and diluted samples were analyzed in a final concentration of 10% matrix. The bioanalytical method was qualified for its intended purpose. The lower limit of quantification (LLOQ) was 400 ng / mL in neat matrix.Results

[0237] In a first experiment, the initial antibody / drug level was at an expected level for three candidates (33733, 32302, and 33628) with acceptable elimination (T’ at 173, 180 and 196 hours, respectively) (FIG. 14A). One candidate (33726) had an unexpectedly rapid elimination; the exposure dropped very rapidly and could not be explained by the presence of anti-drug antibodies (ADA). No animals had a PK profile indicating ADA, and ADA was therefore not assessed.

[0238] In the second experiment, the initial antibody / drug level was at an expected level for five tested antibodies (33628.39191, 33628.39219, 33628.39223, 336287.39230, and 33628.40927) with acceptable elimination (T% at 244, 176, 183, 122, and 155 hours, respectively) (FIG. 14B). 33628.39191 was tested in two separate studies and six of eight mice indicated emergence of ADA after 168 hours, where one of the studies with four mice were confirmed by ADA analysis. One candidate 33627.39218 had a faster elimination, but no indication of ADA emergence was observed. The ATR-107 analogue also had rapid elimination and furthermore indication of ADA emergence after 168 hours (one animal) or 400 hours (3 animals).Example 14: Cryo-EM Structural Epitope Mapping of Antibody 33628

[0239] This work describes the steps undertaken to identify and map the epitope of a Fab of antibody 33628 (“Fab 33628”), targeting the extra cellular domain (ECD) of human IL21R.

[0240] For cryo-EM epitope mapping, a construct of the target antigen (ECD of hIL21R) was designed and construct synthesis, cloning, and protein expression and purification were performed. The ECD of hIL21R was complexed with Fab 33628 and an anti-Fab VHH fragment provided by Servier. Anti-Fab VHH was used in this study to rigidify the Fab backbone by preventing movement of the constant domain as well as facilitating classification and alignment during cryo-EM processing.Materials and MethodsProtein design for structural studies

[0241] The DNA encoding the wild-type extracellular domain of human IL21R (Uniprot Q9HBE5) was cloned into a pCDNA3.4 vector containing an expression cassette with the native or immunoglobulin kappa (IgGK) signal sequence at the N-terminus, followed by a cleavable His-tag at the C-terminus (Table 16). The amino acid sequences of the Fab heavy and light chains, as well as the anti-Fab VHH, are also shown in Table 16.Table 16: Sequences of Cryo-EM Protein Constructs ConstructSequencedescriptionMETDTLLLWVLLLWVPGSTGCPDLVCYTDYLQTVICILEMWNLHPSTL TLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSIgGK SS-IL21R (1- VNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYE 232)-TEV-10His DPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFR KDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGENLYFQ GSGSHHHHHHHHHH ( SEQ ID NO : 53 ) QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLE WFGSISYSGRTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYFab 33628, Heavy CARREAAAGTGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA chain ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTGGSGHHHHHH(SEQ ID NO : 54 ) EIVLTQTPATLSLSPGERATLSCRASQSVSSFLAWYQQKPGQAPRLLI YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSRTFGFab 33628, LightQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQchain WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO : 55 ) GQVQLQESGGGLVQPGGSLRLSCAASGRTISRYAMSWFRQAPGKEREFanti-Fab VHH VAVARRSGDGAFYADSVQGRFTVSRDDAKNTVYLQMNSLKPEDTAVYY CAIDSDTFYSGSYDYWGQGTQVTVSS ( SEQ ID NO : 56)Protein expression and purification

[0242] The final dataset is a merged one resulting from two individual datasets, one with an IL21R-ECD:Fab 33628:anti-Fab VHH complex containing IL21R-ECD (1-232) produced in Expi293F™ cells, and one where the complex contains instead IL21R-ECD (1-232) produced in HEK293 GnTI- cells. For this reason, protein production and grid preparation are described below for both complexes.

[0243] For IL21R-ECD protein expression, the best construct and conditions for subsequent protein production were identified in small-scale expression studies. For large scale production, Expi293F™ cells were grown in 5 L to a cell density of 3.14 xlO6cells / mL in Expi293F™ media at 36.5°C and 5% COS. The cells were transfected withExpiFectamine™ 293 Reagent and 1 mg / mL of DNA followed by 25 mL of ExpiFectamine™ 293 Enhancer 1 and 250 mL of ExpiFectamine™ 293 Enhancer 2 after 18-20 hours post-transfection. Cells were removed 96 hours post-transfection, by centrifugation at 7,000 g for 15 minutes at 4°C. The supernatant containing secreted protein was collected and supplemented with 1 tablet of EDTA-Free cOmplete™ per 50 mL.

[0244] In addition, expression of IL21R-ECD (1-232) in HEK293 GnTI- cells was conducted to reduce the glycosylation of IL21R-ECD. The protein was expressed in 0.25 L of HEK293 GnTI- cells in conditions similar to expression in Expi293F™ cells, except for the following differences: FreeStyle™ 293 Expression Medium + 2% FBS was used for the expression medium, 750 pL PEI-MAX® was used for transfection, and 2.5 mL of 1 M sodium butyrate was used for enhancement.

[0245] To purify the secreted extracellular region of IL21R (1-232) grown in Expi293 F™ cells, 5 L of supernatant was concentrated to approximately 800 mL in a Millipore Pellicon® concentration system using a Biomax Pellicon® 10 kDa membrane. The concentrated supernatant was then purified on a Cytiva HisTrap™ Excel 5 mL column, in PBS pH 7.4, 100 mM NaCl and 5% glycerol, and eluted with a gradient of 5-500 mM imidazole. Fractions containing the protein of interest were confirmed by SDS-PAGE and pooled. The protein was subsequently treated with a 1 :20 ratio of TEV protease (stock solution at 8.15 mg / mL) to remove the affinity tag while simultaneously dialyzing into PBS pH 7.4, 100 mMNaCl, 5% glycerol, 5 mM imidazole at 4 °C for 18 hours. Digestion was confirmed by SDS-PAGE and anti-His Western blot. Subtractive affinity chromatography using a 5 mL Cytiva HisTrap™ Fast Flow Crude column in PBS pH 7.4, 100 mM NaCl, 5% glycerol, was performed and the sample collected from the flowthrough. The protein was concentrated to 5 mg / mL using an Amicon® Ultra-15 Centrifugal Filter Unit with a 10 kDa cut-off and ultracentrifuged at 4°C for 10 minutes at 50,000 g. The protein was subjected to gel filtration using HiLoad® Superdex 200 column 26 / 600 in PBS pH 7.4, 50 mM NaCl buffer. The IL21R-ECD peak was confirmed by SDS-PAGE and pooled. The protein was concentrated from 55 mL to 16 mL using an Amicon® Ultra-15 Centrifugal Filter Unit with a 10 kDa cut-off at 4000 g at 4°C to the final concentration of 1.73 mg / mL. The purity and the size of the final protein were determined by SDS PAGE and analytical SEC, whereas the thermal stability and monodispersity were estimated by dynamic light scattering (DLS) and thermal unfolding (nanoDSF) on a Nanotemper Prometheus Panta.

[0246] Similarly, the extracellular region of IL21R (1-232) from HEK293 GnTI- cells was purified as described above, except with the following changes: the supernatant was notconcentrated before affinity chromatography, the final buffer contained 1% glycerol, and the affinity -tag was not cleaved.Complex formation ofIL21R-ECD:Fab 33628:anti-Fab VHH

[0247] A final concentration of 42 pM of IL21R-ECD:Fab 33628:VHH was produced by mixing all three proteins at 1 : 1 : 1 ratio in PBS pH7.4 buffer. The mixture was incubated on ice for 1 hour before being centrifuged at 30,000 rpm for 10 minutes at 4°C. The protein complex then was concentrated to 6 mg / mL using a Thermo Scientific™ Pierce™ PES protein concentrator with a 10 kDa molecular weight cut-off. The protein complex was subsequently diluted to 2 mg / mL and centrifuged at 30,000 rpm for 10 minutes at 4°C directly before grid preparation.Cryo-EM grid preparation and data collection for IL21R-ECD:Fab 33628:anti-Fab VHH complex

[0248] UltrAuFoil® 300, R0.6 / 1 (for grids with IL21R-ECD expressed in Expi293F™ cells with Fab 33628 and VHH) or UltrAuFoil 300, Rl.2 / 1.3 grids (for grids with IL21R-ECD expressed in HEK293 GnTI- cells with Fab 33628 and VHH) were glow-discharged at 15 mA for 60 s using a PELCO easiGlow™. 3 pL of each sample was pipetted onto to the grids at 4°C with 100% humidity, blotted with a 3 s blot time and -8 blot force, and then plunge-frozen in liquid ethane using a Vitrobot™ Mark IV (Thermo Fisher Scientific, Waltham, MA, USA).Data collection for IL21R-ECD:Fab 33628:anti-Fab VHH complex

[0249] All datasets were collected on a FEI Titan Krios™ G3 microscope (Thermo Fisher Scientific, Waltham, MA, USA) operated at an accelerating voltage of 300 kV in nanoprobe EFTEM mode with a 50 pm C2 aperture at an indicated magnification of 130,000x. Movies were collected on a Gatan K3 electron detector positioned after a Gatan Quantum energy filter (Gatan, Pleasanton, CA, USA), operated in a zero-energy-loss mode. A slit width of 20 eV was used to acquire dose-fractionated images. Movies were recorded as compressed TIFFs in super-resolution mode, binning 2, corresponding to a sampling interval of 0.656 A / pixel with an exposure time of 2 s. Images were recorded at -1 to -2.5 pm defocus. The total exposure corresponded to 68.37 e- / A2, with the exposure rate of 14.7 e- / pixel / s.Data processing of IL21R-ECD with Fab 33628 and anti-Fab VHH

[0250] All data processing was carried out in CryoSPARC v.4.4.1. Two datasets of 8,630 & 16,527 movies were collected and used in the solution of the structure of IL21R-ECD:Fab33628:VHH. Motion correction and CTF estimation using non-dose weighted micrographs was performed for both datasets. Micrographs were curated to exclude micrographs outside a CTF fit of 2-6 A and a relative ice thickness of >1.15. An initial round of Blobpicker and 2D Classification was used to determine IL21R-ECD:Fab 33628:VHH particle locations; the coordinates of which were used to train the neural -network based picker Topaz. The combined particle picks from Topaz and Blobpicker were used for ab initio reconstruction and heterogeneous refinement to produce a consensus particle stack and map reconstruction of the IL21R-ECD:Fab 33628:VHH complex. At this stage, particles from both datasets were merged, resulting in a final particle number of 235,019 particles, and Non-Uniform Refinement was performed. Due to severe orientation bias observed, Rebalance Orientations was run with a rebalance percentile of 80 and intra-bin exclusion of alignments3D / error, followed by Non-Uniform Refinement. The map was post-processed using DeepEMhancer to produce a map suitable for model building.Modelling of IL21R-ECD: Fab 33628:anti-Fab VHH

[0251] A predicted model of Fab 33628 was generated using ABodyBuilder2 from ImmuneBuilder and rigid body fitted into the DeepEMhancer cryo-EM map, along with the published structures of IL21R (PDB ID: 7KQ7) and VHH (PDB ID: 8ACF) using UCSF ChimeraX. Further model building was achieved using Coot, followed by refinement using phenix. real space refine from the PHENIX suite. Model validation was performed using the phenix.validation_cryo-EM tool. The IL21R-ECD:Fab 33628: anti -Fab VHH complex structures were analysed using PyMOL, PISA and ChimeraX.ResultsProduction ofIL21R extracellular domain

[0252] For cryo-EM study, multiple constructs of the ECD of hIL21R with native and IgGK signal sequences were produced for soluble expression of the target protein. Small-scale expression of different constructs was used to determine the best construct for subsequent large-scale production of IL21R-ECD protein.

[0253] hIL21R-ECD was initially expressed in Expi293F™ cells and purified by 3 chromatography steps to high purity. The purified protein showed high level of glycosylation on analytical SEC (aSEC) and SDS-PAGE with observed molecular weights (MW) of 46.6 kDa and 46 kDa respectively, compared to an expected MW of 25.4 kDa. Dynamic Light Scattering (DLS) analysis showed that the cleaved protein in solution is monodisperse, corroborating the symmetrical narrow peak observed on the aSEC profile. The thermalstability of the protein was assessed by nanoDSF and a melting transition (Tm) at 53°C was determined, supporting the use of the reagent in structural study.

[0254] IL21R-ECD was also expressed in HEK293 GnTI- cells with the aim of reducing the glycan heterogeneity of the wild-type protein while maintaining protein stability. As the His-tag was not expected to affect the cryo-EM experiments, the tag was not cleaved in this purification to limit the impact on the final protein yield. Although HEK293 GnTI-expressed protein had no complex glycans, some residual glycosylation was observed. Intact mass spectrometry analysis of the His tagged protein showed predominant peaks at 33.3, 33.5, 33.6 and 33.8 kDa, compared to an expected MW of 27.09 kDa, confirming moderate heterogeneity of the glycosylation state. This result was consistent with the migration profile of the protein on SDS-PAGE, with an estimated MW of 37 kDa. Unlike the fully glycosylated protein, a single melting transition (Tm) at 50°C was observed for the HEK293 GnTI- expressed protein suggesting an influence of the glycans on the thermal profile of the protein. However, the reduced glycosylation pattern of HEK293 GnTI- expressed protein had no impact on the monodispersity of the sample, as determined by DLS analysis.Cryo-EM structure ofIL21R extracellular domain complex with Fab 33628 and an anti-Fab VHHStructure determination of IL21R ECD complexed with Fab 33628 and anti-Fab VHH:

[0255] Cryo-EM single particle analysis was used to determine the molecular structure of the ILR21R-ECD in complex with Fab 33628 and an anti-Fab VHH. The complex was reconstituted by mixing stoichiometric amounts of the individual components followed by plunge-freezing into liquid ethane.

[0256] For IL21R-ECD expressed in Expi293F™ cells, an initial dataset of 8,630 exposures resulted in a 3.7 A map with significant anisotropy which could not be interpreted for model building and refinement. To overcome the preferential orientation causing the anisotropy, IL21R-ECD was expressed in HEK293 GnTI- to truncate the complex-branched glycosylation. A further 16,527 exposures were collected and processed, with new particle views emerging in the 2D class averages. Despite the improvement in the orientations, the data still required balancing by using the dedicated orientation re-balancing tool in CryoSPARC. The two datasets were merged followed by de-noising and B-factor sharpening by the program DeepEMhancer. The final reconstruction has an FSC(0.143) resolution of 3.0 A with clear isotropic density for the side-chains.

[0257] For model building, IL21R-ECD from the protein data bank (PDB: 7KQ7) was used as the initial model, and Servier generated a model for Fab 33628 by using the software MOE (Molecular Operating Environment from CCG) as the initial Fab model. The epitopeparatope region was rebuilt de novo as the local resolution was high enough to unambiguously assign side-chain conformations. Outside the epitope-paratope region, the density of the IL21R-ECD is not well defined owing to the flexibility of domains I and II relative to each other. Despite this, the full IL21R-ECD has been retained to facilitate interpretation of the model. This is justified as the high-resolution crystal structure correlates with the map and there is no evidence of a conformational change in the IL21R-ECD. The model-to-map correlation coefficients for the IL21R-ECD and Fab 33628 are 0.72 and 0.62, respectively. There is density near the putative glycosylation site Asnl06. This region of density is less well resolved - likely due to flexibility - and therefore has not been included in the final model (FIG. 15, Panel B).Epitope of IL21R extracellular domain bound to Fab 33628:

[0258] The structure of the hIL21R:Fab 33628:VHH complex revealed that Fab 33628 binds to domain I on the extracellular side of IL21R (FIG. 15). The binding interface overlaps with the IL21 binding area. This clearly indicates that the binding of Fab 33628 precludes cytokine binding. There are no interactions with domain II in the structure; likely allowing conformation freedom for domain II and explaining the lower resolution of domain II in the map.

[0259] The structure allowed identification of the epitope-paratope interactions of the complex (Tables 17 and 18, FIGs. 16 and 17). On Fab 33628, LCDR1, LCDR3 and HCDR2 form the binding interface with IL21R-ECD. LCDR2, HCDR1 and HCDR3 are not shown to make direct interactions, although they contribute to the stability of the FV binding region through intra-protein interactions. The protein-protein interface is generated through a mixture of polar, aliphatic and charge-charge interactions.

[0260] For the whole Fab 33628, 13 H-bonds were identified; notably S28VL:E97ECD, R91VL:D72ECD, Y60VH:D34ECD, R58VH:H68ECD, R58VH:Y36ECD, K66VH:E37ECD, R93VL:D72ECD, S30VL:S190ECD, and S31VL:S190ECD (Table 17).Full details of all the identified binding interactions are summarized in Table 18. In addition to the polar interactions, hydrophobic interactions contribute to the binding, including Fab33628 residues W49VH and F50VH which are packed against IL21R-ECD residues H68 and F69; and F32VL which is positioned between residues A71ECD and S190ECD that areon two different loops. Further statistics of the IL21R-ECD:Fab 33628 structure are depicted in Table 19 (CDR-L1 is LCDR1, CDR-L3 is LCDR3, etc ).Table 17: Polar and Ionic InteractionsFab 33628 IL21R-ECD Energy Dist Area CDR Typeresidue: atom residue:atom (kcal / mol) (A) (A2) CDR-L1 Ser31:OG Hbond Serl90:OG -0.5 3.5 8.78 CDR-L1 Ser30:CB Hbond Glu97:OE2 -0.7 3.86 5.52 CDR-L1 Ser30:OG Hbond Serl90:O -0.6 3.51 15.53 CDR-L1 Ser28:OG Hbond Glu97:OE2 -1.1 2.69 7.45 CDR-L1 Gln27:NE2 Hbond Ser92:O -0.9 3.28 10.6 CDR-L3 Arg93:NHl Ionic Asp34:ODl -1.17 3.72 6.2 CDR-L3 Arg93:NH2 Ionic Asp72:OD2 -14.94 2.76 16.97 CDR-L3 Arg93:NH2 Hbond Asp72:O -1.3 3.11 5.57 CDR-L3 Arg91:NE,NH2 Hbond Asp72:O -7.7 3.06 12.69 CDR-H2 Arg58:NH2 Hbond His68:OH -0.8 4.41 4.73 CDR-H2 Arg58:NHl Hbond Tyr36:OH -0.7 2.9 4.6 CDR-H2 Tyr60:CB Hbond Asp34:ODl -0.9 3.74 4.44 CDR-H2 Thr59:O Hbond Tyr36:CA -0.5 3.19 5.92 CDR-H2 Pro63:CD Hbond Asp34:ODl -1 3.27 10.46 CDR-H2 Lys66:NZ Ionic Glu37:OEl -2.46 3.36 8.37CDR-H2 Lys66:CE,NZ Hbond Glu37:OEl,OE2 -3.3 3.33 6.12Table 18: Interface ResiduesFab 33628 IL21R-ECD Energy Dist Area CDR Typeresidue residue (kcal / mol) (A) (A2) CDR-L1 Gln27 Hbond Ser92 -0.9 3.28 10.57 CDR-L1 Gln27 Distance Ser92 4.4 3.76 44.3 CDR-L1 Ser28 Distance Leu94 -0.1 4.32 4.29 CDR-L1 Ser28 Hbond Glu97 -1.5 3.1 16.93 CDR-L1 Ser28 Distance Glu97 1.33 3.67 26.94 CDR-L1 Val29 Distance Leu94 -0.21 4.41 5.52 CDR-L1 Val29 Distance Glu97 -0.13 4.05 1.05 CDR-L1 Ser30 Distance Leu94 -0.14 4.45 3.07 CDR-L1 Ser30 Hbond Glu97 -0.7 3.86 5.65 CDR-L1 Ser30 Distance Glu97 -0.11 3.8 3.81 CDR-L1 Ser30 Hbond Seri 90 -0.6 3.51 15.37 CDR-L1 Ser31 Hbond Seri 90 -0.5 3.5 18.54 CDR-L1 Ser31 Distance Seri 90 -0.13 3.91 8.36 CDR-L1 Phe32 Distance Ala71 -0.27 3.87 11.69 CDR-L1 Phe32 Distance Leu94 -0.31 4.11 7.14CDR-L1 Phe32 Distance Ala96 0.38 3.51 10.34CDR-L1 Phe32 Distance Seri 90 -0.46 4.16 21.61 CDR-L2 Asp50 Distance Seri 90 0 4.19 38.29 CDR-L3 Arg91 Hbond Asp72 -7.7 3.06 12.42 CDR-L3 Arg91 Distance Asp72 -0.17 4.17 11.79 CDR-L3 Arg91 Distance He74 0.52 3.95 29.01 CDR-L3 Arg91 Distance Leu94 -0.31 3.84 11.32 CDR-L3 Arg93 Ionic Asp34 -1.17 3.72 14.06 CDR-L3 Arg93 Hbond Asp34 -0.7 3.7 27.75 CDR-L3 Arg93 Distance Asp34 -0.45 4.27 8.03 CDR-L3 Arg93 Ionic Asp72 -14.94 2.76 23.84 CDR-L3 Arg93 Hbond Asp72 -1.3 3.11 5.25 CDR-L3 Arg93 Distance Asp72 2.61 3.93 2.58 CDR-H2 Gly57 Distance Tyr36 -0.17 4.06 9.65 CDR-H2 Gly57 Distance Glu38 0.18 3.73 22.89 CDR-H2 Arg58 Distance Tyr36 0.9 4 35.15 CDR-H2 Arg58 Hbond His68 -0.4 2.88 9.01 CDR-H2 Arg58 Distance His68 90.83 3.77 16.17 CDR-H2 Arg58 Distance Phe69 0.17 4.44 0.42 CDR-H2 Arg58 Distance Met70 -0.08 4.48 9.95 CDR-H2 Thr59 Distance Gln35 0.01 4.36 2.59 CDR-H2 Thr59 Hbond Tyr36 -0.5 3.19 6.12 CDR-H2 Thr59 Distance Tyr36 2.14 3.83 10.95 CDR-H2 Thr59 Distance Glu37 0 4.04 3.93 CDR-H2 Thr59 Distance Glu38 0 4.17 19.13 CDR-H2 Tyr60 Hbond Asp34 -0.9 3.74 12.37 CDR-H2 Tyr60 Distance Asp34 -0.29 4.15 17.61 CDR-H2 Tyr60 Distance Tyr36 0.02 4.35 3.04 CDR-H2 Tyr60 Distance Met70 -0.14 4.2 14.61 CDR-H2 Tyr60 Distance Asp73 -0.02 4.23 7.6 CDR-H2 Tyr61 Hbond Asp34 -0.3 3.99 6.73 CDR-H2 Tyr61 Distance Asp34 1.12 3.65 18.04 CDR-H2 Tyr61 Distance Glu37 -0.53 4.13 25.89 CDR-H2 Asn62 Distance Asp34 -0.03 4.31 4.71 CDR-H2 Pro63 Hbond Asp34 -1 3.27 13.09 CDR-H2 Pro63 Distance Asp34 0.04 4.26 9.36 CDR-H2 Lys66 Hbond Glu37 -3.3 3.33 20.69 CDR-H2 Lys66 Ionic Glu37 -2.46 3.36 8.34 CDR-H2 Lys66 Distance Glu37 -0.5 3.99 9.51 CDR-H2 Lys66 Distance Lys40 1.37 3.57 23.52CDR-H3 Alai 03 Distance Met70 -0.1 3.88 28.9Table 19: Statistics of the IL21R-ECD:Fab 33628 Structure Geometry IL21R:FabData IL21R:Fab 33628 :anti-Fab VHH 33628:anti-Fab VHHBond length rmsd 0.002 A Model-to-volume CC 0.70Bond angle rmsd 0.595° IL21R (A) 0.62 MolProbity score 2.28 Fab 33628 heavy chain (H) 0.71Clash score 9.37 Fab 33628 light chain (L) 0.74Rama favoured 91.39 % anti-Fab VHH (X) 0.67Rama outliers 0.40 % FSC model (0.143 / 0.5) 2.0 / 3.6 A*

[0261] LCDR1 and LCDR3 form a positively charged patch that complements the negatively charged surface on IL21R-ECD (FIG. 16 and FIG. 17, Panel B); this includes specific salt-bridges between R93VL:D72ECD, R93VL:D34 ECD and K66 VL:E37 ECD. There is a single salt-bridge on HCDR2 between K66 VH:Glu37ECD.

[0262] A comparison of IL21R-ECD to previously determined structures indicates that HCDR2 binding induces a conformational change in a loop comprised of residues 33-43; this region of the IL21-R-ECD is essential to cytokine binding.Example 15: Evaluation of Anti-KLH IgG Production in KLH Mouse Model with Antibody 33628, ATR-107 Analogue, and Cyclosporin A

[0263] Human CD40 was knocked into C57BL / 6 mice to produce humanized knock-in mice (Biocytogen). Based on weight, mice were randomized (10 mice per group). Keyhole limpet hemocyanin (KLH) (ThermoFisher) emulsified in TiterMax Gold Adjuvant (Sigma-Aldrich) was subcutaneously injected at Day 0 and Day7. Antibody 33628 at 10 mg / kg, ATR-107 analogue at 10 mg / kg, or vehicle were intraperitoneally injected into the mice on a triweekly basis. Cyclosporin A at 100 mg / kg was orally administered to the mice on a daily basis for a total of 14 per os administrations. Blood sampling was performed at Day Minus 2 (D-2), Day 7, and Day 14 and plasma was collected. Anti KLH IgG quantification was performed with an IgG ELISA assay (Life Diagnostics KLHG-1). The experimental design is depicted in FIG. 18.

[0264] Antibody 33628 demonstrated greater efficacy than ATR-107 in suppressing anti- KLH IgG production at Day 14 (FIG. 19).

Claims

87CLAIMS1. An isolated anti-IL21R antibody or antigen-binding portion thereof, wherein the antibody binds specifically to one or more of amino acids D53, Y55, E56, H87, D91, Sill, and El 16 of SEQ ID NO: 57, optionally wherein said antibody binds specifically to 3, 4, 5, 6, or all 7 of said amino acids.

2. The isolated anti-IL21R antibody or antigen-binding portion thereof according to claim 1, which binds specifically to:i) all of amino acids D53, Y55, E56, H87, D91, Sill, and El 16 of SEQ ID NO: 57, or ii) all of amino acids D53, Q54, Y55, E56, E57, H87, F88, M89, A90, D91, 193, Sill, LI 13, Al 15, El 16, and S209 of SEQ ID NO: 57.

3. An isolated anti-IL21R antibody or an antigen-binding portion thereof, wherein the antibody binds to the same epitope as a reference antibody having a heavy chain variable domain (VH) and a light chain variable domain (VL) comprisingSEQ ID NOs: 1 and 2, respectively,SEQ ID NOs: 11 and 12, respectively,SEQ ID NOs: 21 and 22, respectively,SEQ ID NOs: 31 and 32, respectively,SEQ ID NO: 90 and 91, respectively,SEQ ID NO: 96 and 97, respectively,SEQ ID NO: 101 and 102, respectively,SEQ ID NO: 104 and 105, respectively,SEQ ID NO: 108 and 109, respectively, orSEQ ID NO: 112 and 113, respectively.

4. The isolated anti-IL21R antibody or an antigen-binding portion thereof according to claim 3,wherein the antibody binds to the same epitope as a reference antibody having a heavy chain variable domain (VH) and a light chain variable domain (VL) comprising SEQ ID NOs: 1 and 2, respectively, andwherein the epitope comprises (i) all of amino acids D53, Y55, E56, H87, D91, Sill, and88A90, D91, 193, Sill, LI 13, Al 15, El 16, and S209 of SEQ IDNO: 57.

5. The anti-IL21R antibody or antigen-binding portion of any one of claims 3-4, wherein a) the heavy chain of the anti-IL21R antibody comprises:i) heavy chain complementarity determining regions (H-CDR) 1-3 comprising SEQ IDNOs: 3-5, respectively;ii) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1;iii) a VH comprising SEQ ID NO: 1; oriv) SEQ ID NO: 1 and any one of SEQ ID NOs: 41-43 optionally without the C-terminal lysine; andb) the light chain of the anti-IL21R antibody comprises:i) light chain complementarity determining regions (L-CDR) 1-3 comprising SEQ ID NOs: 6-8, respectively;ii) a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2; iii) a VL comprising SEQ ID NO: 2; oriv) SEQ ID NOs: 2 and 44.

6. An anti-IL21R antibody or an antigen-binding portion thereof, wherein the antibody comprises H-CDR1-3 and L-CDR1-3 amino acid sequences of:a) SEQ ID NOs: 3-8, respectively;b) SEQ ID NOs: 13-18, respectively;c) SEQ ID NOs: 23-28, respectively;d) SEQ ID NOs: 33-38, respectively;e) SEQ ID NOs: 92-95, 114 and 8, respectively;f) SEQ ID NOs: 98-99, 5, 100, 115 and 8, respectively;g) SEQ ID NOs: 3, 93, 5, 103, 116 and 8, respectively;h) SEQ ID NOs: 106, 93, 5, 107, 116, and 8, respectively;i) SEQ ID NOs: 110, 93, 5, 111, 114, and 8, respectively; orj) SEQ ID NOs: 3, 93, 5, 6-8, respectively.

7. The anti-IL21R antibody or antigen-binding portion of claim 6, wherein the antibody comprises a heavy chain variable domain (VH) amino acid sequence and a light chain variable89domain (VL) amino acid sequence that are at least 90% identical to the amino acid sequences of:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively,e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

8. The anti-IL21R antibody or antigen-binding portion of claim 6 or 7, wherein the antibody comprises a VH and a VL comprising:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 12, respectively;c) SEQ ID NOs: 21 and 22, respectively;d) SEQ ID NOs: 31 and 32, respectively,e) SEQ ID NO: 90 and 91, respectively,f) SEQ ID NO: 96 and 97, respectively,g) SEQ ID NO: 101 and 102, respectively,h) SEQ ID NO: 104 and 105, respectively,i) SEQ ID NO: 108 and 109, respectively, orj) SEQ ID NO: 112 and 113, respectively.

9. The anti-IL21R antibody of any one of claims 1-8, wherein the antibody is of isotype subtype IgGi.

10. The anti-IL21R antibody of claim 9, wherein the antibody comprises a mutant Fc domain with reduced binding affinity for an Fc gamma receptor.

11. The anti-IL21R antibody of claim 10, wherein the mutant Fc domain hasa) mutations L234A and L235A (Eu numbering), or90b) mutations L234A, L235E, and G237A (Eu numbering).

12. The anti-IL21R antibody of any one of claims 1-8, wherein the antibody comprises a heavy chain constant region comprising SEQ ID NO: 43 optionally without the C-terminal lysine.

13. An anti-IL21R antibody that comprises:a) a heavy chain (HC) comprising SEQ ID NO: 62 optionally without the C-terminal lysine, and a light chain (LC) comprising SEQ ID NO: 63;b) an HC comprising SEQ ID NO: 64 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 65;c) an HC comprising SEQ ID NO: 66 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 67; ord) an HC comprising SEQ ID NO: 68 optionally without the C-terminal lysine, and an LC comprising SEQ ID NO: 69e) an HC comprising SEQ ID NO: 117 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 118;f) an HC comprising SEQ ID NO: 119 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 120;g) an HC comprising SEQ ID NO: 121 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 122; orh) an HC comprising SEQ ID NO: 123 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 124;i) an HC comprising SEQ ID NO: 125 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 126; orj) an HC comprising SEQ ID NO: 127 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 128.

14. The anti-IL21R antibody according to any one of claims 1-13, which is less polyreactive than ATR-107 and / or C2 antibody, optionally wherein ATR-107 antibody comprises a HC sequence comprising SEQ ID NO: 45, and a LC sequence comprising SEQ ID NO: 46, and C2 antibody comprises a HC sequence comprising SEQ ID NO: 51, and a LC sequence comprising SEQ ID NO: 52.9115. A bispecific binding molecule comprising a binding portion of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14 and a binding portion of another, distinct antibody.

16. A pharmaceutical composition comprising the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14 or the bispecific binding molecule of claim 15, and a pharmaceutically acceptable excipient.

17. Isolated nucleic acid molecule(s) comprising a nucleotide sequence that encodes the heavy chain sequence, and a nucleotide sequence that encodes the light chain sequence, of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14.

18. The isolated nucleic acid molecule(s) of claim 17, wherein the nucleic acid molecule(s) comprise a nucleotide sequence selected from SEQ ID NOs: 9, 10, 19, 20, 29, 30, 39, 40, 70, 71, 72, 73, 74, 75, 76, 77, 78, 84, 79, 85, 80, 86, 81, 87, 82, 88, 83 and 89.

19. Vector(s) comprising the isolated nucleic acid molecule(s) of claim 17 or 18, wherein the vector(s) further comprise an expression control sequence.

20. A host cell comprising a nucleotide sequence that encodes the heavy chain sequence, and a nucleotide sequence that encodes the light chain sequence, of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14.

21. A method for producing an anti-IL21R antibody or an antigen-binding portion thereof, comprisingproviding a host cell of claim 20,culturing said host cell under conditions suitable for expression of the antibody or antigen-binding portion, andisolating the resulting antibody or antigen-binding portion.

22. A method of treating an autoimmune or inflammatory condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16.9223. The anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16, for use in treating an autoimmune or inflammatory condition in a patient in need thereof.

24. Use of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16, in the manufacture of a medicament for treating an autoimmune or inflammatory condition in a patient in need thereof.

25. The method of claim 22, the anti-IL21R antibody or antigen-binding portion or bispecific binding molecule or pharmaceutical composition for use of claim 23, or the use of claim 24, wherein the condition is selected from the group consisting of graft-versus-host disease (GvHD), asthma, allergic asthma, chronic spontaneous urticaria (CSU), diabetes (optionally type 1 diabetes or latent autoimmune diabetes), lupus (optionally systemic lupus erythematosus or lupus nephritis), arthritis (optionally rheumatoid arthritis or juvenile arthritis), giant cell arteritis, allergy, antibody-mediated rejection, organ graft rejection, transplant desensitization, Addison’s disease, ankylosing spondylitis, anti-glomerular basement membrane disease, IgA nephropathy, autoimmune hepatitis, primary biliary cholangitis (PBC), celiac disease, autoimmune alopecia, atopic dermatitis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, granulomatosis with polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, autoimmune thyroid disease (AITD), antiphospholipid syndrome, hemolytic anemia, Henoch-Schonlein purpura, juvenile myositis, Kawasaki disease, inflammatory bowel disease (optionally Crohn’s disease or ulcerative colitis), multiple sclerosis, myasthenia gravis, neuromyelitis optica, psoriasis, psoriatic arthritis, Sjogren’s syndrome, systemic scleroderma, systemic sclerosis, immune thrombocytopenia (ITP), thrombocytopenic purpura, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, uveitis, autoimmune uveitis, thyroid eye disease, vasculitis, vitiligo, neuromyelitis optica spectrum disorder (NMOSD), encephalitis, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), amyotrophic lateral sclerosis (ALS), and Vogt-Koyanagi -Harada Disease.

26. The method of claim 22, the anti-IL21R antibody or antigen-binding portion or bispecific binding molecule or pharmaceutical composition for use of claim 23, or the use of93claim 24, wherein the condition is graft-versus-host disease (GvHD).

27. The method of claim 22, the anti-IL21R antibody or antigen-binding portion or bispecific binding molecule or pharmaceutical composition for use of claim 23, or the use of claim 24, wherein the condition is pemphigus vulgaris, autoimmune hepatitis, vitiligo, antibody-mediated rejection, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

28. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16.

29. The anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16, for use in treating cancer in a patient in need thereof.

30. Use of the anti-IL21R antibody or antigen-binding portion of any one of claims 1-14, the bispecific binding molecule of claim 15, or the pharmaceutical composition of claim 16, in the manufacture of a medicament for treating cancer in a patient in need thereof.

31. The method of claim 28, the anti-IL21R antibody or antigen-binding portion or bispecific binding molecule or pharmaceutical composition for use of claim 29, or the use of claim 30, wherein the cancer is multiple myeloma or diffuse large B cell lymphoma(DLBCL).

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