Treatment of t-cell mediated inflammatory and / or autoimmune disease

Abstract

Provided are compounds, compositions and methods for treating a T-cell mediated inflammatory and / or an autoimmune disease in patients in need thereof.

Description

132301-11320TREATMENT OF T-CELL MEDIATED INFLAMMATORY AND / OR AUTOIMMUNE DISEASEREFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of the filing date of U.S.Provisional Patent Application Nos. 63 / 743,727, filed on Jan. 10, 2025, and 63 / 754,108, filed on February 5, 2025. This application is also related to U.S. Provisional Application No. 63 / 516,535, filed on July 31, 2023, and International Patent Application No.PCT / US2024 / 040285, filed on July 31, 2024. The entire contents of each of the above applications are incorporated herein by reference.

[0002] Interleukin-7 (IL-7) is a member of the common y chain (yc) family of cytokines that also includes IL-2, IL-4, IL-9, IL-15, and IL-21. Like other members, IL-7 signals via a ternary complex formed with its unique a-receptor, IL-7Ra (CD127), and the common y receptor (yc, CD132). IL-7 regulates T-cell homeostasis by enhancing survival and proliferation of naive and memory T cells; however, it appears to be dispensable for B cell development in humans. IL-7Ra is expressed on T cells including most mature T cells, on dendritic cells (DCs) and activated monocytes.

[0003] IL-7 / IL-7R interaction stimulates the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins with subsequent activation of the phosphoinositol 3-kinase (PI3K) / Akt, or Src pathways to facilitate target gene transcription. IL-7 Ra is also used by thymic stromal-derived lymphopoietin (TSLP) as part of a complex that contains a second receptor chain, TSLPR.

[0004] The TSLPR complex contains CD 127 and TSLPR (CRLF2), and is expressed on several types of immune cells, including B cells, T cells, monocytes and DCs. TSLP has been shown to be a potent activator of antigen presenting cells such as DCs to induce TH2-mediated immune responses. For example, TSLP- stimulated DCs increase OX40L expression and production of TH2 chemokines, such as CCL17 and CCL21, leading to the priming of TH2 cell development.

[0005] IL-7 plays a critical role in the development of a normal immune system, as it is essential for the thymic development, peripheral maintenance, and survival of lymphocytes. Thymic T cell precursors require IL-7 for proliferation, differentiation, and survival. In the1MEl\59465771.vl132301-11320periphery, IL-7 regulates T cell hemostasis by enhancing the survival and proliferation of naive and memory T cells.

[0006] IL-7 is a tissue-derived cytokine and is primarily produced from stromal and epithelial cells in various tissues. For instance, in the small and large intestines, IL-7 is produced by the intestinal goblet epithelial cells and has been described as being essential for the persistence of chronic colitis in animal models. IL-7 has also been shown to interfere with the immunosuppressive capabilities of regulatory T cells (Tregs). Thus, agents that can modulate the activity of IL-7 in vivo and thereby decrease the survival / function of pathogenic T cells and / or increase the induction of regulatory T cells are highly desirable for the treatment of inflammatory diseases, such as inflammatory bowel disease.

[0007] There is a need to develop effective treatment for T-cell mediated inflammatory and / or an autoimmune disease.SUMMARY

[0008] Provided herein is a method of treating a T-cell mediated inflammatory and / or an autoimmune disease in a subject (e.g., a human) in need thereof, the method comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT).

[0009] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is not atopic dermatitis or alopecia areata (AA).

[0010] In certain embodiments, the composition comprising the antibody is administered to the subject to maintain serum concentration of the antibody at >5 pg / mL throughout dosing, such that the T-cell mediated inflammatory and / or an autoimmune disease is treated in the subject.

[0011] In certain embodiments, the antibody has a heavy chain sequence of SEQ ID NO: 23 and a light chain sequence of SEQ ID NO: 24.

[0012] In certain embodiments, the method rebalances Teff / mem and Tregfunction in the subject.2MEl\59465771.vl132301-11320

[0013] In certain embodiments, the method (1) significantly reduces CD3+T cells from baseline in the subject, and / or (2) significantly reduces a Th2 biomarker in the subject, wherein the Th2 biomarker is selected from the group consisting of: eosinophil count, TARC level, and IgE level.

[0014] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is a CD3+-driven disease, a Th 1 -driven disease, a Th2-driven disease, a disease driven by both Thl and Th2, or a CD8+T cell-driven inflammation.

[0015] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is EGPA (eosinophilic granulomatosis with polyangiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), EoE (eosinophilic esophagitis), AtD, COPD (chronic obstructive pulmonary disease), asthma, alopecia, UC (ulcerative colitis), celiac disease, vitiligo, MS (multiple sclerosis), RA (rheumatoid arthritis), HS (hidradenitis suppurativa), T1D (type 1 diabetes), LN (lupus nephritis), SLE, or Autoimmune Hepatitis.

[0016] In certain embodiments, the method inhibits Th2-mediated inflammation and treats an eosinophilic disease.

[0017] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is an eosinophilic disease selected from the group consisting of: EGPA (eosinophilic granulomatosis with polyangiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), and EoE (eosinophilic esophagitis).

[0018] In certain embodiments, the antibody is administered to the subject subcutaneously ( .c.).

[0019] In certain embodiments, the antibody is administered once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every eight weeks (Q8W), once every twelve weeks (Q12W), or any intermittent PRN (pro re natd).

[0020] In certain embodiments, the antibody is administered for 5-25 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) consecutive doses.

[0021] In certain embodiments, the antibody is formulated as 100 mg / mL solution in 20 mM histidine, 260 mM sucrose, and 0.05% (w / v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.

[0022] In certain embodiments, the subject has impaired renal function (e.g., mildly impaired renal function (such as a glomerular filtration rate <60 mL / min and / or the presence of albuminuria >30 mg / d), moderately impaired renal function (such as a glomerular filtration3MEl\59465771.vl132301-11320rate <45 mL / min), or severely impaired renal function (such as a glomerular filtration rate <30 mL / min).

[0023] In certain embodiments, the subject is further being treated by or has been treated by a second therapeutic agent effective to treat the T-cell mediated inflammatory and / or an autoimmune disease.

[0024] It should be understood that any embodiment described herein, including those described only in the examples, can be combined with any one or more other embodiments, unless such combination is expressly disclaimed or is improper. Thus, the term “embodiment”, as used herein, is not to be considered as excluding features recited in other embodiments.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIGs. 1A-1C show effects of prophylactic treatment with COMPOUND A (Comp. A) and a comparator IL-7Ra antibody (A3312F) in the Hu-NSG mouse model of GvHD on body weight loss (FIG. 1A), plasma cytokine levels (ELISA) (FIG. IB) and percent human T cells (CD45+ CD3+) in blood as measured by flow cytometry (FIG. 1C). Measurements were determined 21 days post PBMC transfer. Abbreviations: CCL1: antimicrobial protein with bactericidal activity; CD: cluster differentiation; GvHD: graft-versus host disease; Hu-NSG: humanized nod / SCID / IL2rynull; IFN: interferon; IL-7Ra: interleukin-7 receptor alpha; IP: intraperitoneal; PBMC: peripheral blood mononuclear cells; TNF: tumor necrosis factor.

[0026] FIGs. 2A-2B show target engagement and inhibition of pSTAT5 levels on human T cells in blood (FIG. 2A) and spleens (FIG. 2B) of Hu-NSG mice after treatment with (Comp. A) (18B1), a comparator IL-7Ra antibody (A3312F) or vehicle (PBS). Antibodies were administered in vivo at concentrations of 0.2, 1, and 5 mg / kg. IL-7-induced pSTAT5 was evaluated in an ex vivo assay and included a non-targeting IL-7 negative control sample (CTL Unstim). Abbreviations: CTL: control; Hu-NSG: Hu-NSG: humanized nod / SdD / IL2rynull; IL-7Ra: interleukin-7 receptor alpha; MFI: mean fluorescence intensity; PBS: phosphate buffered saline; pSTAT5: phosphorylated signal transducer and activator of transcription 5.

[0027] FIGs. 3A and 3B show data after administration of single ascending dose (SAD; 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg) and multiple doses (MAD; 1 mg / kg) in phase 1 clinical data in human (see Example 8). FIG. 3A shows percentage of IL-7 receptor occupancy (RO) in CD3+ T cells, and FIG. 3B shows percentage of inhibition of IL-7 signaling via phosphorylated STAT5 (pSTAT5) in T cells.4MEl\59465771.vl132301-11320

[0028] FIG. 4A shows data (Mean ± SD) on serum concentration profile in patients with topic dermatitis (AD) after subcutaneous administration of COMPOUND A at doses of 2 or 3 mg / kg every 2 weeks. SD: standard deviation. 5 pg / mL represents the concentration with predicted maximum receptor occupancy in skin.

[0029] FIG. 4B shows preliminary data (mean ± SD) on IL-7Ra receptor occupancy (RO) on circulating CD3+ T cells in patients with atopic dermatitis (AD) after subcutaneous administration of COMPOUND A at doses of 2 or 3 mg / kg every 2 weeks. RO: receptor occupancy; SD: standard deviation. Dashed vertical lines represent the dosing days.

[0030] FIG. 4C shows preliminary data (mean ± SD) of serum concentration profile and of IL-7Ra receptor occupancy (RO) on circulating CD3+ T cells in patients with atopic dermatitis (AD) after subcutaneous administration of COMPOUND A at doses of 200mg every 2 weeks (Q2W) over 12 weeks (z.e., dosing every 2 weeks for a total of 7 doses, with the first dose on Day 1 and the last dose on Day 85, or the last dose on Day 84 as nominal time after the 1st dose on Day 0). SD: standard deviation. 5 pg / mL represents the concentration with predicted maximum receptor occupancy in skin. 90% RO represents maximal receptor occupancy.

[0031] FIGs. 5A-5C show data of certain representative T-cells changes (FIG. 5B-5C) and Th2 biomarker (FIG. 5A) in participants of SIGNAL- AA (FIG. 5B) and SIGNAL- AtD (FIG. 5A-5C) trial after treatment with COMPOUND A / Bempikibart or placebo.

[0032] FIG. 6 shows data of adverse events through week 24.DETAILED DESCRIPTION

[0033] Provided herein is a method of treating a T-cell mediated inflammatory and / or an autoimmune disease in a subject (e.g., a human) in need thereof, the method comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT).

[0034] In certain embodiments, the antibody for IL-7Ra is COMPOUND A, a high affinity effector-minimized anti-IL-7Ra antagonist antibody that blocks the IL-7 cytokine 5MEl\59465771.vl132301-11320binding to human IL-7Ra (CD 127) and inhibits IL-7 receptor (IL-7R) (CD 127 / CD 132) mediated intracellular signaling pathways. It exhibits high affinity as an anti-interleukin-7 receptor a (IL-7Ra) and reduced affinity to FcyR (Type I, II, or III), the receptors that mediate effector functions, and to complement component 1 (Clq), the mediator of complement cell lysis. In addition to forming the heterodimeric IL-7R, the IL-7Ra chain heterodimerizes with TSLPR(CRLF2) to form a high affinity TSLP receptor (TSLPR) complex. TSLP is an epithelial-cell-derived cytokine that promotes inflammation in response to environmental stimuli. While COMPOUND A also inhibits TSLPR activity on monocytes in vitro, studies to date have been focused on the effects of COMPOUND A on IL-7R -mediated activity in vitro and in vivo.

[0035] Nonclinical pharmacology studies confirm IL-7Ra receptor occupancy (RO) and inhibition of IL-7Ra-mediated pharmacodynamic (PD) responses and T-cell mediated biology. Both interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) receptors are heterodimeric, and share the common IL-7Ra subunit.

[0036] In a Phase 1 study in healthy participants, COMPOUND A single doses up to 4 mg / kg and repeat doses of 1 mg / kg every two weeks were safe and well tolerated. Results from that Phase 1 study demonstrated that doses of COMPOUND A that achieved >95% receptor occupancy were associated with >90% inhibition of IL-7 signaling via phosphorylation of signal transducer and activator of transcription-5 (STAT5). Repeat administration of COMPOUND A at 1 mg / kg demonstrated durable inhibition of IL-7Ra after the 2nd dose over the 2-week dose regimen. In addition, the lymphocyte subsets and T cell immune function assessments exhibited modest, dose-dependent effects on these biomarkers. Based on the available nonclinical and Phase 1 safety data, no expected adverse events have been identified. Thus, the Phase 1 study has shown that COMPOUND A have acceptable tolerability and safety, has confirmed the expected pharmacology, and has allowed for the generation of a predictive pharmacokinetic (PK)-PD model, supporting initiation of the further clinical study.

[0037] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is not atopic dermatitis or alopecia areata (AA).

[0038] In certain embodiments, the composition comprising the antibody is administered to the subject to maintain serum concentration of the antibody at >5 pg / mL throughout dosing, such that the T-cell mediated inflammatory and / or an autoimmune disease is treated in the subject.6MEl\59465771.vl132301-11320

[0039] In some embodiments, the VH CDR1 comprises SEQ ID NO: 7 (GFTFDDHAMH).

[0040] In some embodiments, the antibody has a heavy chain sequence of SEQ ID NO: 23 and a light chain sequence of SEQ ID NO: 24.

[0041] In certain embodiments, the method rebalances Teff / mem and Tregfunction in the subject.

[0042] In certain embodiments, the method (1) significantly reduces CD3+T cells from baseline in the subject, and / or (2) significantly reduces a Th2 biomarker in the subject, wherein the Th2 biomarker is selected from the group consisting of: eosinophil count, TARC level, and IgE level.

[0043] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is a CD3+-driven disease, a Th 1 -driven disease, a Th2-driven disease, a disease driven by both Thl and Th2, or a CD8+T cell-driven inflammation.

[0044] In certain embodiments, a CD3+-driven disease includes a CD3+T-cell-mediated inflammatory and / or autoimmune diseases, such as one due to overactivation of CD3 in the TCR, leading to autoreactive T-cells that cause chronic inflammation and tissue damages. Representative CD3+-driven disease include SLE, Rheumatoid Arthritis, Multiple Sclerosis, Autoimmune Hepatitis, and Type 1 Diabetes.

[0045] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is EGPA (eosinophilic granulomatosis with poly angiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), EoE (eosinophilic esophagitis), AtD, COPD (chronic obstructive pulmonary disease), asthma, alopecia, UC (ulcerative colitis), celiac disease, vitiligo, MS (multiple sclerosis), RA (rheumatoid arthritis), HS (hidradenitis suppurativa), T1D (type 1 diabetes), LN (lupus nephritis), SLE, or Autoimmune Hepatitis.

[0046] In certain embodiments, the method inhibits Th2-mediated inflammation and treats an eosinophilic disease.

[0047] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is an eosinophilic disease selected from the group consisting of: EGPA (eosinophilic granulomatosis with polyangiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), and EoE (eosinophilic esophagitis).

[0048] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis or Churg-Strauss syndrome, which is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in 7MEl\59465771.vl132301-11320persons with a history of airway allergic hypersensitivity (atopy). The disease typically manifests in three stages, but not all patients develop all three stages or progress from one stage to the next in the same order. The early (prodromal) stage is marked by airway inflammation; almost all patients experience asthma and / or allergic rhinitis. The second stage is characterized by abnormally high numbers of eosinophils (hypereosinophilia), which causes tissue damage, most commonly to the lungs and the digestive tract. The third stage consists of vasculitis, which can eventually lead to cell death and can be life-threatening. Effective treatment of EGPA may require suppression of the immune system, such as using glucocorticoids (such as prednisolone), followed by other agents such as cyclophosphamide or azathioprine.

[0049] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is eosinophilic esophagitis (EoE) which is an emerging disease with a constantly increasing prevalence. It represents a chronic inflammatory disorder with narrowing or stricture of the esophagus. EoE has a prominent esophageal eosinophilia (>20 peak eosinophil number per high power field (hpf)), often affecting the entire esophagus. Adult EoE is considered to be a T helper 2 (Th2)-type allergic disease, whereby aeroallergens play a key pathogenic role. The inflammation in the gastrointestinal tract is restricted to the esophagus and does not affect the stomach, small intestine and colon. However, patients with EoE may also suffer from additional allergic diseases of the respiratory tract.

[0050] EoE is the result of a dysregulated Th2 immune response to dietary and aeroallergens that yields exclusive esophageal inflammation and dysfunction. It shares the same triggers and downstream agents typically associated with other Th2 conditions, and similarly also responds to glucocorticoid therapy. The esophageal mucosa of active EoE patients contains activated Th2 cells that secrete increased levels of the TNF-related cytokine LIGHT, an inflammatory cytokine that converts resident esophageal mucosal fibroblasts to the fibrostenosing phenotype. Furthermore, the activated fibroblasts have been shown to migrate to the epithelium where they directly interact with eosinophils (Rabinowitz et al. EoE behaves as a unique Th2 disease: a narrative review. Transl Gastroenterol Hepatol. 2023 Jan 25;8:11).

[0051] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is chronic rhinosinusitis with nasal polyps (CRSwNP) which is an inflammatory disease of the mucosa lining the nasal cavity and paranasal sinuses, and is estimated to affect up to 4% of the adult population. The characteristic nasal polyps (NPs) are benign, edematous, inflammatory lesions that originate from the mucosa of the paranasal sinuses 8MEl\59465771.vl132301-11320(mainly ethmoid) and can obstruct both the nasal airway and the olfactory cleft.

[0052] The main symptoms of CRSwNP are nasal congestion, rhinorrhea, and loss of smell. Smell loss has a significant negative impact on health-related quality of life (HRQoL) and is reported by patients to be one of the most important and troublesome symptoms of their disease. Patients with CRSwNP experience a high symptom burden, which significantly impacts both their mental and their physical HRQoL. Furthermore, patients often have coexisting inflammatory respiratory diseases, notably asthma and nonsteroidal antiinflammatory drug-exacerbated respiratory disease (NSAID-ERD). The standard of care for CRSwNP includes intranasal corticosteroids and saline irrigation. Sinonasal surgery or oral steroids are needed for patients with uncontrolled and more severe disease. However, recurrence is common, with up to 40% of patients needing further surgery within 18 months. Oral steroids may provide short-term relief, although repeated courses are associated with adverse effects including but not limited to weight gain, high blood pressure, and an increased risk of infections.

[0053] Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. (Bachert, Claus, et al. "The interleukin-4 / interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps." Frontiers in Immunology 15 (2024): 1356298.).

[0054] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is hidradenitis suppurativa (HS) (also known as acne inversa or Vemeuil's disease) which is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lumps. HS may significantly limit many everyday activities, including walking, hugging, moving, and sitting down. Sitting disability may occur in patients with lesions in 9MEl\59465771.vl132301-11320sacral, gluteal, perineal, femoral, groin or genital regions; and prolonged periods of sitting down can also worsen the condition of the skin of these patients.

[0055] Hidradenitis suppurativa is a chronic inflammatory disorder, which affects the intertriginous skin and is associated with numerous systemic comorbidities. The estimated prevalence of HS is ~1% in most studied countries. Typically starting in early adulthood, cutaneous inflamed nodules, abscesses and pus-discharging tunnels develop in axillary, inguinal, gluteal and perianal body sites. The comorbidities of HS include metabolic and cardiovascular disorders, which contribute to reduced life expectancy. A genetic predisposition, smoking, obesity and hormonal factors are established aetiological factors for HS. Cutaneous changes seem to start around hair follicles and involve activation of cells of the innate and adaptive immune systems, with pivotal roles for pro -inflammatory cytokines such as tumour necrosis factor, IL-ip and IL-17. The unrestricted and chronic immune response eventually leads to severe pain, pus discharge, irreversible tissue destruction and scar development.

[0056] The immune system plays a key role also in the progression and chronification of skin alterations. Innate proinflammatory cytokines (e.g. interleukin- 113 and tumour necrosis factor-a), mediators of activated T helper (Th)l and Thl7 cells (e.g. interleukin- 17 and interferon-y), and effector mechanisms of neutrophilic granulocytes, macrophages and plasma cells are involved. Simultaneously, skin lesions contain anti-inflammatory mediators (e.g. interleukin- 10) and show limited activity of Th22 and regulatory T cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction and scarring. Chronic inflammation in patients with HS is also frequently detected in organs other than the skin, as indicated by their comorbidities.

[0057] In certain embodiments, the T-cell mediated inflammatory and / or an autoimmune disease is celiac disease (CD) which is a T-cell mediated immune disease in which gliadin-derived peptides activate lamina propria effector CD4+ T cells. This activation leads to the release of cytokines, compatible with a Thl-like pattern, which play a crucial role in the pathogenesis of CD, controlling many aspects of the inflammatory immune response. Recent studies have shown that a novel subset of effector T cells, characterized by expression of high levels of IL-17A, termed Thl7 cells, plays a pathogenic role in CD. While these effector T cell subsets produce proinflammatory cytokines, which cause substantial tissue injury in vivo in CD, recent studies have suggested the existence of additional CD4+ T cell subsets with suppressor functions. These subsets include type 1 regulatory T cells and CD25+CD4+10MEl\59465771.vl132301-11320regulatory T cells, expressing the master transcription factor Foxp3, which have important implications for disease progression.

[0058] Role of TH1 cells in CD: Although the innate immune response is a prerequisite for the excessive activation of adaptive immunity, the latter is the more proximate driver of the tissue damage that manifests in CD patients. Upon activation, gliadin- specific CD4+ T cells polarize along the T helper (Th) 1-type pathway, substantiated by an ability to produce large amounts of IFN-y, the signature cytokine of Thl responses. mRNA for IFN-y is more increased in untreated disease than the message for IL-2, IL- 18, and TNF-a. Furthermore, the IFN-y mRNA levels in the biopsies of treated patients have been demonstrated to reach that of untreated patients by in vitro stimulation with gliadinf 18]. Therefore, IFN-y might be much more involved in the generation of gliadin-driven mucosal damage in CD, as indicated by the efficacy of anti-IFN-y antibodies in preventing villous atrophy.

[0059] In some embodiments, the antibody is administered to the subject subcutaneously (5.C.).

[0060] In some embodiments, the antibody is administered once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every eight weeks (Q8W), once every twelve weeks (Q12W), or any intermittent PRN (pro re natd).

[0061] In some embodiments, each administration, starting from the second dose, is separated from the immediate prior administration by the same number of days, preferably around the same time of the day of the administration.

[0062] In some embodiments, the antibody is administered once every two weeks, preferably, each administration starting from the second dose is separated by 14 days from the immediate prior administration, preferably around the same time of the day of the administration.

[0063] In certain embodiments, the antibody is administered for 5-25 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) consecutive doses.

[0064] In some embodiments, the antibody is formulated as 100 mg / mL solution in 20 mM histidine, 260 mM sucrose, and 0.05% (w / v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.

[0065] In some embodiments, the antibody is administered to the subject based on a weight-based dosing regimen.

[0066] In some embodiments, the antibody is administered to the subject based on a body surface area (BSA)-based dosing regimen. For example, the dose for an adult male patient of 11MEl\59465771.vl132301-11320any weight (in kg) and height (in cm) can be calculated / converted, based on a BSA Base Dose used for a standard male weight of 91 kg and height of 175 cm, to reach a dose of about 10 mg - about 800 mg per dose, about 20 mg - about 500 mg per dose, about 50 mg - about 300 mg per dose, about 100 mg - about 250 mg per dose.

[0067] In some embodiments, the antibody is administered to the subject based on a weight-banded dosing regimen, in which patients within certain ranges of weights (weightbands) are dosed a fixed amount for that specific weight band.

[0068] In some embodiments, the subject has impaired renal function (e.g., mildly impaired renal function (such as a glomerular filtration rate <60 mL / min and / or the presence of albuminuria >30 mg / d), moderately impaired renal function (such as a glomerular filtration rate <45 mL / min), or severely impaired renal function (such as a glomerular filtration rate <30 mL / min). In other embodiments, the subject is normal, e.g., normal with respect to renal function.

[0069] In some embodiments, the subject is an adult e.g., 18 years and older).

[0070] In some embodiments, the subject is not an adult, or is a pediatric patient or an adolescent patient (e.g., a patient of under 18-year old, under 16-year old, under 14-year old, under 12-year old, under 10-year old, under 5-year old, under 3-year old, under 2-year old, under 1-year old, under 6-month old, or under 3-month old).

[0071] In some embodiments, the subject is a Caucasian. In some embodiments, the subject is Asian. In some embodiments, the subject is African. In some embodiments, the subject is native American. In some embodiments, the subject is of mixed race or ethnic group. In some embodiments, the subject is biologic male. In some embodiments, the subject is biologic female.

[0072] In some embodiments, the subject is further being treated by or has been treated by a second therapeutic agent effective to treat the T-cell mediated inflammatory and / or an autoimmune disease.

[0073] In some embodiments, the method reduces the measurement of a T-cell mediated inflammatory and / or an autoimmune disease-associated biomarker after treatment (compared to before treatment).

[0074] In some embodiments, the method further comprises detecting in the individual a T-cell mediated inflammatory and / or an autoimmune disease-associated biomarker, either before or after treatment, or both.

[0075] In some embodiments, prior to administering the subject anti-IL-7Ra antibody, antigen binding fragment thereof, or a pharmaceutically acceptable salt thereof, to the12MEl\59465771.vl132301-11320individual, the method further comprises selecting the individual based on a level of a T-cell mediated inflammatory and / or an autoimmune disease-associated biomarker.

[0076] In some embodiments, the administration of the subject anti-IL-7Ra antibody, antigen binding fragment thereof, or a pharmaceutically acceptable salt thereof, results in a change in a level of a T-cell mediated inflammatory and / or an autoimmune disease-associated biomarker in the individual.

[0077] In some embodiments, the composition comprising the antibody is administered to the subject to maintain serum concentration of the antibody at >5 pg / mL throughout dosing.

[0078] Serum concentration of the antibody can be measured using any methods known in the art. For example, the level of the anti-IL-7Ra antibody in serum can be determined using a target capture approach. Specifically, the serum is flowed through a surface (e.g., column) pre-coated with a capture agent specific for the anti-IL-7Ra antibody (e.g., human IL-7R extracellular domain), and the antibody in the serum is captured onto the surface. After washing off unbound materials, a labeled secondary antibody that specifically binds to the anti-IL-7Ra antibody but does not compete for binding with the capture agent (e.g., a labeled secondary antibody which binds to the Fc region of the anti-IL-7Ra antibody) is added to detect the presence of the anti-IL-7Ra antibody captured by the pre-coated substrate. Signal intensity from the labeled secondary antibody is proportional to the concentration of the anti-IL-7Ra antibody in the serum, and serum concentration of the antibody is determined by comparing its measured signal to signals produced by standards with known concentrations of the antibody.

[0079] In a non-limiting example, serum concentration of the antibody can be measured using a Gyrolab® system which is a flow through immunoassay platform. In this fit-for-purpose assay, the antibody present in serum is captured on the columns in the Gyrolab® CD, which is pre-coated with biotinylated recombinant human IL-7R extracellular domain (target). The bound anti-IL-7Ra antibody is detected with AlexaFluor®-647 labeled Cyno anti-human IgG Fc mAb (Pur Clone 10C7). The immunofluorescence measured using the Gyrolab® ’s laser-induced fluorescence (LIF) detector is proportional to the concentration of the anti-IL-7Ra antibody in samples, standards, and controls.

[0080] In another non-limiting example, serum concentration of the antibody can be measured using a Gyrolab® system, which is a flow through immunoassay platform. In this validated assay, the antibody present in serum is captured on the columns in the Gyrolab® CD which is pre-coated with biotinylated anti-idiotypic monoclonal antibody (mAb) that specifically bind to the anti-IL-7Ra antibody. The bound anti-IL-7Ra antibody is detected 13MEl\59465771.vl132301-11320with AlexaFluor®-647 labeled mAb which is a non-competing clone but also binds to anti-IL-7Ra antibody. The immunofluorescence measured using the Gyrolab®’ s LIF detector is proportional to the concentration of the anti-IL-7Ra antibody in samples, standards, and controls.

[0081] In some embodiments, the subject has an absolute lymphocyte count (ALC) of > 800 per microL.

[0082] In some embodiments, administration of the antibody is stopped when the subject’s ALC is < 500 per microL.

[0083] In some embodiments, the antibody comprises an effectorless IgGl Fc.

[0084] The definitions and methods provided define the present disclosure and guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0085] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.”

[0086] As used herein, the term “about” is construed to include all values less than a full increment and greater than a full decrement of the least significant digit claimed. In other words, the term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[0087] As used herein, the term “disease-associated biomarker,” for T-cell mediated inflammatory and / or autoimmune disease, means any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule which is present or detectable in a patient having the T-cell mediated inflammatory and / or autoimmune disease, at a level or amount that is different from (e.g., greater than or less than) the level or amount of the marker present or detectable in a normal control subject. The term “disease-associated biomarker” also includes a gene or gene probe known in the art which is differentially expressed in a subject with the T-cell mediated inflammatory and / or autoimmune disease, as compared to a subject without the disease. Alternatively, “disease-associated biomarker” for T-cell mediated inflammatory 14MEl\59465771.vl132301-11320and / or autoimmune disease also includes genes which are down regulated due to the T-cell mediated inflammatory and / or autoimmune disease.

[0088] Exemplary disease-associated biomarkers for T-cell mediated inflammatory and / or autoimmune diseases include one or more of: total eosinophil count, total IgE (e.g., high total serum IgE levels), CCL17 (Thymus and Activation-Regulated Chemokine (TARC)), CCL18 (PARC), LDH (lactate dehydrogenase), serum levels of CD30, Macrophage-Derived Chemoattractant (MDC), interleukins (IL)-12, IL-16, IL-18, IL-31, and filaggrin gene null mutations.

[0089] In some embodiments, disease-associated biomarkers for T-cell mediated inflammatory and / or autoimmune disease include one or more of: total eosinophil count, total IgE, CCL17 (TARC), CCL18 (PARC), and / or LDH.

[0090] In some embodiments, the biomarker comprises total eosinophil count. In some embodiments, the biomarker comprises total IgE. In some embodiments, the biomarker comprises CCL17. In some embodiments, the biomarker comprises CCL18. In some embodiments, the biomarker comprises LDH.

[0091] In some embodiments, the biomarker is assessed using histology. In some embodiments, the biomarker is assessed using RNAseq. In some embodiments, the biomarker is assessed using proteomic analysis. In some embodiments, the biomarker is assessed using enzyme-linked immunosorbent assay. In some embodiments, the biomarker is assessed using mass spectrometry. In some embodiments, the biomarker is assessed using a blood sample. In some embodiments, the biomarker will be assessed using a serum sample. In some embodiments, the biomarker will be assessed using a plasma sample. In some embodiments, the biomarker is assessed using a tissue sample. In some embodiments, the biomarker will be assessed using a punch biopsy.

[0092] In some embodiments, the biomarker is a gene expression signature.

[0093] Also provided are biomarkers for monitoring disease reversal with the administration of the subject antibody, or a pharmaceutically acceptable formulation thereof. Methods for detecting and / or quantifying such disease-associated biomarkers are known in the art; kits for measuring such disease-associated biomarkers are available from various commercial sources; and various commercial diagnostic laboratories offer services which provide measurements of such biomarkers as well.

[0094] As used herein, “TSLP” refers to a growth factor that closely resembles IL-7 and plays a role in the maturation and activation of myeloid cells (e.g., monocytes and dendritic cells). TSLP is produced by various cell types, such as fibroblasts, epithelial cells, and15MEl\59465771.vl132301-11320stromal cells. Elevated levels of TSLP have been associated with diseases, such as asthma, atopic dermatitis, and inflammatory arthritis, which are also known to be associated with abnormal regulation of IL-7.

[0095] As used herein, the term “antibody” refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). In certain antibodies, e.g., naturally occurring IgG antibodies, the heavy chain constant region is comprised of a hinge and three domains, CHI, CH2 and CH3. In certain antibodies, e.g., naturally occurring IgG antibodies, each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain (abbreviated herein as CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. A heavy chain may have the C-terminal lysine or not. Unless specified otherwise herein, the amino acids in the variable regions are numbered using the Rabat numbering system and those in the constant regions are numbered using the EU system. “Antibody” includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and nonhuman antibodies and wholly synthetic antibodies.

[0096] An “IgG antibody”, e.g., a human IgGl, IgG2, IgG3 and IgG4 antibody, as used herein, has, in some embodiments, the structure of a naturally occurring IgG antibody, i.e., it has the same number of heavy and light chains and disulfide bonds as a naturally occurring IgG antibody of the same subclass. For example, an anti-IL-7R IgGl, IgG2, IgG3 or IgG4 antibody consists of two heavy chains (HCs) and two light chains (LCs), wherein the two heavy chains and light chains are linked by the same number and location of disulfide bridges that occur in naturally occurring IgGl, IgG2, IgG3 and IgG4 antibodies, respectively (unless the antibody has been mutated to modify the disulfide bridges).16MEl\59465771.vl132301-11320

[0097] Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (KD) of 10’5to 1011M or less. Any KD greater than about 10’4M is generally considered to indicate nonspecific binding.

[0098] In some embodiments, the anti-IL-7Ra antibody used or useful for the method described herein specifically binds to IL-7Ra, such as binding specifically with a KD of 10’5to 1011M or less (e.g., 10’5M or less, 10’6M or less, 10’7M or less, 10’8M or less, 10’9M or less, IO’10M or less, or 10’11M or less).

[0099] In some embodiments, the anti-IL-7Ra antibody used or useful for the method described herein binds specifically to IL-7Ra (such as human IL-7Ra) with a KD of 10’7M or less, 10’8M or less, 5 x 10’9M or less, or between 10’8M and IO10M or less, but does not bind with high affinity to unrelated antigens.

[0100] An antigen is “substantially identical” to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the sequence of the given antigen. By way of example, an antibody that binds specifically to human IL-7Ra can, in some embodiments, also have cross-reactivity with IL-7Ra antigens from certain primate species (e.g., cynomolgus IL-7Ra), but cannot cross-react with IL-7Ra antigens from other species or with an antigen other than IL-7Ra.

[0101] As used herein, “isotype” refers to the antibody class (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant region genes. The IgG isotype is divided in subclasses in certain species: IgGl, IgG2, IgG3 and IgG4 in humans, and IgGl, IgG2a, IgG2b and IgG3 in mice. In some embodiments, the anti-IL-7R antibodies described herein are of the IgGl isotype. Immunoglobulins, e.g., IgGl, exist in several allotypes, which differ from each other in at most a few amino acids.

[0102] As used herein, the term “allotype” refers to naturally occurring variants within a specific isotype group, wherein the variants differ in a few amino acids. Anti-IL-7R antibodies described herein can be of any allotype. As used herein, antibodies referred to as “IgGlf,” “IgGl. If,” or “IgG1.3f” isotype are IgGl, effectorless IgGl.l, and effectorless IgG1.3 antibodies, respectively, of the allotype “f,” i.e.. having 214R, 356E and 358M according to the EU index as in Kabat, as shown, e.g., in SEQ ID NO: 23.

[0103] The term “antigen-binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human IL-7Ra). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments17MEl\59465771.vl132301-11320encompassed within the term “antigen-binding portion” of an antibody, e.g., an anti-IL-7R antibody described herein, include (i) a Fab fragment (fragment from papain cleavage) or a similar monovalent fragment consisting of the VL, VH, LC and CHI domains; (ii) a F(ab')2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fa fragment consisting of the VH and CHI domains; (iv) a 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; (vi) an isolated complementarity determining region (CDR) and (vii) a combination of two or more isolated CDRs which can optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for 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 regions pair to form monovalent molecules (known as single chain Fv (scFv). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody.

[0104] These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0105] The term “monoclonal antibody,” as used herein, refers to an antibody from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprised in the population are substantially similar and bind the same epitope(s) e.g., the antibodies display a single binding specificity and affinity), except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0106] The term “human monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies that display(s) a single binding specificity and which has variable and optional constant regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.18MEl\59465771.vl132301-11320

[0107] The term “recombinant human antibody,” as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies comprise variable and constant regions that utilize particular human germline immunoglobulin sequences are encoded by the germline genes, but include subsequent rearrangements and mutations which occur, for example, during antibody maturation. As known in the art, the variable region contains the antigen binding domain, which is encoded by various genes that rearrange to form an antibody specific for a foreign antigen. In addition to rearrangement, the variable region can be further modified by multiple single amino acid changes (referred to as somatic mutation or hypermutation) to increase the affinity of the antibody to the foreign antigen. The constant region will change in further response to an antigen (z.e., isotype switch). Therefore, the rearranged and somatically mutated nucleic acid molecules that encode the light chain and heavy chain immunoglobulin polypeptides in response to an antigen cannot have sequence identity with the original nucleic acid molecules, but instead will be substantially identical or similar (z.e., have at least 80% identity).

[0108] A “human” antibody (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The anti-IL-7R antibodies described herein can include amino acid residues not encoded by human germline immunoglobulin sequences e.g., mutations introduced by random or site- specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms “human” antibodies and “fully human” antibodies are used synonymously.

[0109] A “humanized” antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with19MEl\59465771.vl132301-11320corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen. A “humanized” antibody retains an antigenic specificity similar to that of the original antibody.

[0110] A “chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

[0111] The phrases “an antibody recognizing an antigen” and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”

[0112] An “isolated antibody,” as used herein, is intended to refer to an antibody which is substantially free of other proteins and cellular material.

[0113] As used herein, an antibody that “inhibits binding of IL-7 to IL-7Ra” is intended to refer to an antibody that inhibits the binding of IL-7Ra to its ligand, e.g., interleukin-7 (IL-7), e.g., in binding assays using T cells from whole blood that express IL-7Ra, with an EC50 of about 1 pg / mL or less, such as about 0.9 pg / mL or less, about 0.85 pg / mL or less, about 0.8 pg / mL or less, about 0.75 pg / mL or less, about 0.7 pg / mL or less, about 0.65 pg / mL or less, about 0.6 pg / mL or less, about 0.55 pg / mL or less, about 0.5 pg / mL or less, about 0.45 pg / mL or less, about 0.4 pg / mL or less, about 0.35 pg / mL or less, about 0.3 pg / mL or less, about 0.25 pg / mL or less, about 0.2 pg / mL or less, about 0.15 pg / mL or less, about 0.1 pg / mL or less, or about 0.05 pg / mL or less, in art-recognized methods, e.g., the FACS-based binding assays described herein.

[0114] An “effector function” refers to the interaction of an antibody Fc region with an Fc receptor or ligand, or a biochemical event that results therefrom. Exemplary “effector functions” include Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, FcyR-mediated effector functions such as ADCC and antibody dependent cell-mediated phagocytosis (ADCP), and downregulation of a cell surface receptor (e.g., the B cell receptor; BCR). Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain).20MEl\59465771.vl132301-11320

[0115] An “Fc receptor” or “FcR” is a receptor that binds to the Fc region of an immunoglobulin. FcRs that bind to an IgG antibody comprise receptors of the FcyR family, including allelic variants and alternatively spliced forms of these receptors. The FcyR family consists of three activating (FcyRI, FcyRIII, and FcyRIV in mice; FcRIA, FcRIIA, and FcyRIIIA in humans) and one inhibitory (FcyRIIB) receptor. Various properties of human FcyRs are known in the art. The majority of innate effector cell types coexpress one or more activating FcyR and the inhibitory FcyRIIB, whereas natural killer (NK) cells selectively express one activating Fc receptor (FcyRIII in mice and FcyRIIIA in humans) but not the inhibitory FcyRIIB in mice and humans. Human IgGl binds to most human Fc receptors and is considered equivalent to murine IgG2a with respect to the types of activating Fc receptors that it binds to.

[0116] An “Fc region” (fragment crystallizable region) or “Fc domain” or “Fc” refers to the C-terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (Clq) of the classical complement system. Thus, an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CHI or CF). In IgG, IgA and IgD antibody isotypes, the Fc region comprises two identical protein fragments, derived from the second (CH2) and third (CH3) constant domains of the antibody's two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. For IgG, the Fc region comprises immunoglobulin domains CH2 and CH3 and the hinge between CHI and CH2 domains. Although the definition of the boundaries of the Fc region of an immunoglobulin heavy chain might vary, as defined herein, the human IgG heavy chain Fc region is defined to stretch from an amino acid residue D221 for IgGl, V222 for IgG2, F221 for IgG3 and P224 for IgG4 to the carboxy-terminus of the heavy chain, wherein the numbering is according to the EU index as in Kabat. The CH2 domain of a human IgG Fc region extends from amino acid 237 to amino acid 340, and the CH3 domain is positioned on C-terminal side of a CH2 domain in an Fc region, i.e., it extends from amino acid 341 to amino acid 447 or 446 (if the C-terminal lysine residue is absent) or 445 (if the C-terminal glycine and lysine residues are absent) of an IgG. As used herein, the Fc region can be a native sequence Fc, including any allotypic variant, or a variant Fc (e.g., a non-naturally occurring Fc). Fc can also refer to this region in isolation or in the context of an Fc-comprising protein polypeptide such as a “binding protein comprising an Fc region,” also referred to as an “Fc fusion protein” (e.g., an antibody or immunoadhesion).21MEl\59465771.vl132301-11320

[0117] A “native sequence Fc region” or “native sequence Fc” comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgGl Fc region; native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof. Native sequence Fc include the various allotypes of Fes.

[0118] The term “epitope” or “antigenic determinant” refers to a site on an antigen (e.g., IF-7Ra) to which an immunoglobulin or antibody specifically binds, e.g., as defined by the specific method used to identify it. Epitopes can be formed both from contiguous amino acids (usually a linear epitope) or noncontiguous amino acids juxtaposed by tertiary folding of a protein (usually a conformational epitope). Epitopes formed from contiguous amino acids are typically, but not always, retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation. Methods for determining what epitopes are bound by a given antibody (z.e.. epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, wherein overlapping or contiguous peptides from e.g., from IF-7Ra) are tested for reactivity with a given antibody (e.g., anti-IF-7R antibody). Methods of determining spatial conformation of epitopes include techniques in the art and those described herein, for example, x-ray crystallography, antigen mutational analysis, 2-dimensional nuclear magnetic resonance and HDX-MS.

[0119] The term “kassoc” or “ka”, as used herein, is intended to refer to the association rate of a particular antibody- antigen interaction, whereas the term “kdis” or “ka,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term “KD”, as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of kd to ka (i.e.. kd / ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. Available methods for determining the KD of an antibody include surface plasmon resonance, a biosensor system such as a BIACORE® system or flow cytometry and Scatchard analysis.

[0120] As used herein, the term “high affinity” for an IgG antibody refers to an antibody having a KD of 10’8M or less, 10’9M or less, or IO10M or less for a target antigen. However, “high affinity” binding can vary for other antibody isotypes. For example, “high affinity” binding for an IgM isotype refers to an antibody having a KD of IO10M or less, or 10’8M or less.22MEl\59465771.vl132301-11320

[0121] The term “EC50” in the context of an in vitro or in vivo assay using an antibody or antigen binding fragment thereof, refers to the concentration of an antibody or an antigenbinding portion thereof that induces a response that is 50% of the maximal response, i.e., halfway between the maximal response and the baseline.

[0122] As used herein, the term “autoimmune disease” refers to a disease or disorder in which the immune system produces an immune response (e.g., a B cell or a T cell response) against an antigen that is part of the normal host (i.e., an autoantigen), with consequent injury to tissues. An autoantigen may be derived from a host cell, or may be derived from a commensal organism such as the micro-organisms (known as commensal organisms) that normally colonize mucosal surfaces.

[0123] The term “inflammation” or an “inflammatory process,” as used herein, refers to a complex series of events, including dilatation of arterioles, capillaries and venules, with increased permeability and blood flow, exudation of fluids, including plasma proteins and leukocyte migration into the inflammatory focus. Inflammation may be measured by many methods well known in the art, such as the number of leukocytes, the number of polymorphonuclear neutrophils (PMN), a measure of the degree of PMN activation, such as luminal enhanced-chemiluminescence, or a measure of the amount of proinflammatory cytokines (e.g., IL-6 or TNF-a) present.

[0124] As used herein, the term “regulatory T cells” (Tregs) refer to a population of T cells with the ability to reduce or suppress the induction and proliferation of effector T cells, and thereby, modulate an immune response. In some embodiments, Tregs can suppress an immune response by secreting anti-inflammatory cytokines, such as IL-10, TGF-b, and IL-35, which can interfere with the activation and differentiation of naive T cells into effector T cells. In some embodiments, Tregs can also produce cytolytic molecules, such as Granzyme B, which can induce the apoptosis of effector T cells. In some embodiments, the regulatory T cells are natural regulatory T cells (nTregs) (i.e.. developed within the thymus). In some embodiments, the regulatory T cells are induced regulatory T cells (iTregs) (i.e., naive T cells that differentiate into Tregs in the peripheral tissue upon exposure to certain stimuli).Methods for identifying Tregs are known in the art. For example, Tregs express certain phenotypic markers (e.g., CD25, Foxp3, or CD39) that can be measured using flow cytometry. In some embodiments, the Tregs are CD45RA- CD39+ T cells.

[0125] As used herein, “administering” refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Different routes of administration for 23MEl\59465771.vl132301-11320the anti-IL-7R antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation. Alternatively, an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0126] As used herein, the terms “inhibits” or “blocks” (e.g., referring to inhibition / blocking of binding of IL-7 to IL-7Ra on cells) are used interchangeably and encompass both partial and complete inhibition / blocking. In some embodiments, the anti-IL-7R antibody inhibits binding of IL-7 to IL-7Ra by at least about 50%, for example, about 60%, 70%, 80%, 90%, 95%, 99%, or 100%, determined, e.g., as further described herein.

[0127] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease or enhancing overall survival. These terms do not include prophylatic intervention.

[0128] The term “prophylatic intervention” refers to treating a subject who does not yet have a disease for preventive purpose.

[0129] The term “effective dose” or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve a desired effect.

[0130] A “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent e.g., the subject anti-IL-7Ra antibody) is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. A therapeutically effective amount or dosage of a drug includes a “prophylactically effective amount” or a “prophylactically effective dosage,” which is any 24MEl\59465771.vl132301-11320amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease. The ability of a therapeutic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials (including the methods described in the examples), in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0131] The term “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. In some embodiments, the patient is a human.

[0132] As used herein, the term “subject” includes any human or non-human animal. For example, the methods and compositions described herein can be used to treat a subject having cancer. The term “non-human animal” includes all vertebrates, e.g., mammals and nonmammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.

[0133] The term “weight-based” dose or dosing as referred to herein means that a dose that is administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg / kg of an anti-IL-7R antibody, one can calculate and use the appropriate amount of the anti-IL-7Ra antibody (z.e., 180 mg) for administration.

[0134] Provided are methods for the treatment of a T-cell mediated inflammatory and / or autoimmune disease, the method comprising administering to a subject in need thereof an isolated antibody or antigen binding portion thereof, which specifically binds to an alphachain of a human IL-7 receptor (“anti-IL-7Ra antibody,” or “anti-IL-7R antibody” for short), comprising a heavy chain CDR1, CDR2, and CDR3, and a light chain CDR1, CDR2, and CDR3, respectively, wherein the antibody(a) is capable of binding to T cells (CD4+CD45RA+, CD4+CD45RA", CD8+CD45RA+, and / or CD8+CD45RA ) in whole blood with an EC50 of about 5 nM or less e.g., less than about 3 nM);(b) is not capable of binding to non-T cells in whole blood;(c) does not agonize IL-7 receptor signaling upon binding to the IL-7 receptor, e.g., minimal pSTAT5 activation; or(d) any combination thereof.25MEl\59465771.vl132301-11320

[0135] In some embodiments, the heavy chain CDR3 of the subject anti-IL-7Ra antibody (e.g., disclosed herein) comprises the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV).

[0136] In some embodiments, the anti-IL-7Ra antibody has one or more properties selected from the group consisting of:(a) is capable of selectively binding to an alpha-chain of a human and cynomolgus IL-7 receptor (IL-7R);(b) is capable of binding to an alpha-chain of soluble and membrane bound IL-7R; (c) is capable of blocking an expansion and / or survival of pathogenic T cells when administered to a subject in need thereof;(d) is capable of restoring a T regulatory cell (Treg) function and / or promoting a Treg survival when administered to a subject in need thereof;(e) is capable of maintaining a drug free remission longer than that by CTLA4-Ig (ORENCIA®);(f) is capable of blocking inflammation and mucosal damage, e.g., induced by pathogenic T cells, within an intestinal tissue of a subject in need thereof;(g) is capable of decreasing a frequency of T effector cells in the mesenteric lymph nodes (MLN) and / or lamina propria (LP) in a subject in need thereof;(h) is capable of reducing or inhibiting IL-7 mediated pSTAT activation in T cells (e.g., CD4+CD45RA+);(i) is capable of blocking expansion of IL- 17 and / or IFN-gamma producing cells; (j) is capable of treating a subject with an inflammatory disease e.g., inflammatory bowel disease); and(k) any combination thereof.

[0137] In some embodiments, the subject anti-IL-7Ra antibody comprises a heavy chain CDR1, wherein the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (DHAMH), such as any one of amino acid sequences set forth in SEQ ID NOs: 7 to 22. In some embodiments, an anti-IL-7Ra antibody comprises a heavy chain CDR2, wherein the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2 (GISWNSRGIGYADSVKG). In some embodiments, an anti-IL-7Ra antibody comprises a heavy chain CDR3, wherein the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV). In some embodiments, an anti-IL-7Ra26MEl\59465771.vl132301-11320antibody comprises a light chain CDR1, wherein the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4 (RASQGISSALA). In some embodiments, an anti-IL-7Ra antibody comprises a light chain CDR2, wherein the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5 (DASSLES). In some embodiments, an anti-IL-7Ra antibody comprises a light chain CDR3, wherein the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6 (QQFNSYPLWIT).

[0138] In some embodiments, the subject anti-IL-7Ra antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 (e.g., any one of SEQ ID NOs: 7-22, such as SEQ ID NO: 7 (GFTFDDHAMH)); a heavy chain CDR2 of the amino acid sequence set forth in SEQ ID NO: 2 (GISWNSRGIGYADSVKG); a heavy chain CDR3 of the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV); a light chain CDR1 of the amino acid sequence set forth in SEQ ID NO: 4 (RASQGISSALA); a light chain CDR2 of the amino acid sequence set forth in SEQ ID NO: 5 (DASSLES); and a light chain CDR3 of the amino acid sequence set forth in SEQ ID NO: 6 (QQFNSYPLWIT).

[0139] In some embodiments, the subject anti-IL-7Ra antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the VL comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 26.

[0140] In some embodiments, the subject anti-IL-7Ra antibody disclosed herein specifically binds to the alpha-chain of the human IL-7 receptor at an epitope selected from the group consisting of:24SQLEVNGSQHSLTCAF39(SEQ ID NO: 27);73FIETKKFLLIGKSNIC88(SEQ ID NO: 28);89VKVGEKSLTCKKIDLTT105(SEQ ID NO: 29);136QKKYVKVLMHDVAY149(SEQ ID NO: 30);181YEIKVRSIPDHYFKGF196(SEQ ID NO: 31); and combinations thereof.

[0141] In some embodiments, an anti-IL-7Ra antibody specifically binds to the alphachain of the human IL-7 receptor at an epitope comprising one or more amino acid residues selected from the group consisting of H33, E75, F79, 182, K84, M144, R186, H191, Y192, and combinations thereof.27MEl\59465771.vl132301-11320

[0142] In some embodiments, an anti-IL-7R antibody of is selected from the group consisting of an IgGl, IgG2, IgG3, IgG4, and a variant thereof.

[0143] In some embodiments, an IL-7R antibody is an IgGl antibody. In some embodiments, an anti-IL-7R antibody comprises an effectorless IgGl Fc.

[0144] In some embodiments, the subject anti-IL-7Ra antibody or antigen binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0145] In some embodiments, the subject anti-IL-7Ra antibody or antigen binding portion thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 23 and wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 24.

[0146] In some embodiments, an anti-IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.3 nM), as measured by surface plasmon resonance. In some embodiments, an anti-IL-7Ra antibody binds to the alpha-chain of the cynomolgus IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.7 nM), as measured by surface plasmon resonance. In some embodiments, the binding to the alpha-chain of the human IL-7 receptor or the alpha-chain of the cynomolgus IL-7 receptor is pH-dependent. In some embodiments, an anti-IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of about 1.3 nM at pH 7.4 and with a KD of about 5.3 nM at pH 6. In some embodiments, an anti-IL-7Ra antibody binds to the alphachain of the cynomolgus IL-7 receptor with a KD of about 1.7 nM at pH 7.4 and with a KD of about 7.0 nM at pH 6.

[0147] In some embodiments, the isolated antibody or antigen binding portion thereof, which specifically binds to an alpha-chain of a human IL-7 receptor (“anti-IL-7Ra antibody”) comprising a heavy chain (HC) CDR1, CDR2, and CDR3, and a light chain (LC) CDR1, CDR2, and CDR3, wherein: (i) the heavy chain CDR1 comprises an amino acid sequence set forth in any one of SEQ ID NOs: 7 to 22; (ii) the heavy chain CDR2 comprises an amino acid sequence set forth in SEQ ID NO: 2 (GISWNSRGIGYADSVKG); (iii) the heavy chain CDR3 comprises an amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV); (iv) the light chain CDR1 comprises an amino acid sequence set forth in SEQ ID NO: 4 (RASQGISSALA); (v) the light chain CDR2 comprises an amino acid sequence set forth in SEQ ID NO: 5 (DASSLES); and (vi) the light chain CDR3 comprises an amino acid28MEl\59465771.vl132301-11320sequence set forth in SEQ ID NO: 6 (QQFNSYPLWIT). In certain aspects, the heavy chain CDR1 comprises an amino acid sequence set forth in SEQ ID NO: 8 (GYTFDDHAMH), SEQ ID NO: 19 (GFDFDDHAMH), or SEQ ID NO: 20 (GFEFDDHAMH).

[0148] The relevant sequences of the exemplary antibodies are provided below.

[0149] Table 1: Amino acid sequences of anti- IL-7Ra antibodies29MEl\59465771.vl132301-11320

[0150] In some embodiments, the anti-IL-7Ra antibody binds to the alpha-chain of the human IL-77Ra with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.3 nM), as measured by surface plasmon resonance. In some embodiments, an anti-IL-7Ra antibody binds to the alpha-chain of the cynomolgus IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.7 nM), as measured by surface plasmon resonance. In some embodiments, the binding to the alpha-chain of the human IL-7 receptor or the alpha-chain of the cynomolgus IL-7 receptor is pH-dependent. In some embodiments, an anti- IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of about 1.3 nM at pH 7.4 and with a KD of about 5.3 nM at pH 6. In some embodiments, an anti-IL-7R antibody binds to the alphachain of the cynomolgus IL-7 receptor with a KD of about 1.7 nM at pH 7.4 and with a KD of about 7.0 nM at pH 6.

[0151] In some embodiments, an anti-IL-7Ra antibody is formulated for administration to the subject at a flat dose or a body weight-based dose. In some embodiments, an anti-IL-7Ra antibody is formulated for administration to the subject at a body weight-based dose (e.g., mg / kg). In some embodiments, an anti-IL-7Ra antibody is formulated for administration intravenously, subcutaneously, intramuscularly, intradermally, or intraperitoneally. In some embodiments, an anti-IL-7Ra antibody is formulated for administration intravenously (z.v.) or subcutaneously (s.c.).

[0152] Provided herein are compositions comprising an anti-IL-7Ra antibody or antigenbinding portion thereof described herein having the desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic30MEl\59465771.vl132301-11320polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt- forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG).

[0153] In a specific embodiment, pharmaceutical compositions comprise an antibody or antigen binding portion thereof, a bispecific molecule, or a immunoconjugate described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. In a specific embodiment, pharmaceutical compositions comprise an effective amount of an antibody or antigen-binding portion thereof described herein, and optionally one or more additional prophylactic of therapeutic agents, in a pharmaceutically acceptable carrier. In some embodiments, the antibody is the only active ingredient included in the pharmaceutical composition. Pharmaceutical compositions described herein can be useful in modulating (e.g., reducing or inhibiting) IL-7 activity in a T cell (e.g., pathogenic T cell) and treating a disease or disorder, such as an inflammatory disease, e.g., inflammatory bowel disease.

[0154] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, immunoconjugate, or bispecific molecule, can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.

[0155] Also provided is a pharmaceutical formulation, which improves the stability of the anti-IL-7Ra antibodies and thus, allows for their long-term storage. In some embodiments, the pharmaceutical formulation disclosed herein comprises: (a) an anti-IL-7R antibody; (b) a buffering agent; (c) a stabilizing agent; (d) a salt; (e) a bulking agent; and / or (f) a surfactant. In some embodiments, the pharmaceutical formulation is stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years or more. In some embodiments, the formulation is stable when stored at 4°C, 25°C, or 40°C.31MEl\59465771.vl132301-11320

[0156] Buffering agents can be a weak acid or base used to maintain the acidity (pH) of a solution near a chosen value after the addition of another acid or base. Suitable buffering agents can maximize the stability of the pharmaceutical formulations by maintaining pH control of the formulation. Suitable buffering agents can also ensure physiological compatibility or optimize solubility. Rheology, viscosity and other properties can also dependent on the pH of the formulation. Common buffering agents include, but are not limited to, histidine, citrate, succinate, acetate and phosphate. In some embodiments, a buffering agent comprises histidine (e.g., L-histidine) with isotonicity agents and potentially pH adjustment with an acid or a base known in the art. In some embodiments, the buffering agent is L- histidine. In some embodiments, the pH of the formulation is maintained between about 2 and about 10, or between about 4 and about 8.

[0157] Stabilizing agents are added to a pharmaceutical product in order to stabilize that product. Such agents can stabilize proteins in a number of different ways. Common stabilizing agents include, but are not limited to, amino acids such as glycine, alanine, lysine, arginine, or threonine, carbohydrates such as glucose, sucrose, trehalose, raffmose, or maltose, polyols such as glycerol, mannitol, sorbitol, cyclodextrins or dextrans of any kind and molecular weight, or PEG. In some embodiments, the stabilizing agent is chosen in order to maximize the stability of FIX polypeptide in lyophilized preparations. In some embodiments, the stabilizing agent is sucrose and / or arginine.

[0158] Bulking agents can be added to a pharmaceutical product in order to add volume and mass to the product, thereby facilitating precise metering and handling thereof. Common bulking agents include, but are not limited to, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, or magnesium stearate.

[0159] Surfactants are amphipathic substances with lyophilic and lyophobic groups. A surfactant can be anionic, cationic, zwitterionic, or nonionic. Examples of nonionic surfactants include, but are not limited to, alkyl ethoxylate, nonylphenol ethoxylate, amine ethoxylate, polyethylene oxide, polypropylene oxide, fatty alcohols such as cetyl alcohol or oleyl alcohol, cocamide MEA, cocamide DEA, polysorbates, or dodecyl dimethylamine oxide. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80.

[0160] In some embodiments, the pharmaceutical formulation comprises: (a) about 0.25 mg / mL to 250 mg / mL (e.g., 10 to 200 mg / mL) of an anti-IL-7Ra antibody; (b) about 20 mM histidine; (c) about 260 mM sucrose; (d) about 0.5 mM DTPA; and (e) about 0.05% Tween-80; optionally further comprising 0.05 mM pentetic acid.

[0161] In some embodiments, the pharmaceutical formulation comprises about 10032MEl\59465771.vl132301-11320mg / mL of an anti-IL-7Ra antibody in 20 mM histidine, 260 mM sucrose, and 0.05% (w / v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.

[0162] The formulation can further comprise one or more of a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer and / or a surfactant, as well as various combinations thereof. The use of preservatives, isotonic agents, chelating agents, stabilizers and surfactants in pharmaceutical compositions is well-known to the skilled person.

[0163] In some embodiments, the pharmaceutical formulation is an aqueous formulation. Such a formulation is typically a solution or a suspension, but may also include colloids, dispersions, emulsions, and multi-phase materials. The term "aqueous formulation" is defined as a formulation comprising at least 50% w / w water. Likewise, the term "aqueous solution" is defined as a solution comprising at least 50 % w / w water, and the term "aqueous suspension" is defined as a suspension comprising at least 50 % w / w water.

[0164] In some embodiments, the pharmaceutical formulation is a freeze-dried formulation, to which the physician or the patient adds solvents and / or diluents prior to use.

[0165] Pharmaceutical compositions described herein also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an IL-7R antibody described herein combined with at least one other therapeutic agent. Examples of therapeutic agents that can be used in combination therapy can include other compounds, drugs, and / or agents used for the treatment of a disease or disorder (e.g., an inflammatory disorder). Such compounds, drugs, and / or agents can include, for example, anti-inflammatory drugs or antibodies that block or reduce the production of inflammatory cytokines. In some embodiments, therapeutic agents can include an anti -IP- 10 antibody, an anti-TNF-a antibody (e.g., adalimumab (HUMIRA®), golimumab (SIMPONI®), infliximab (REMICADE®), certolizumab pegol (CIMZIA®)), interferon beta-la (e.g., AVONEX®, REBIF®), interferon beta- lb e.g., BETASERON®, EXT AVIA®), glatiramer acetate (e.g., COPAXONE®, GLATOPA®), mitoxantrone (e.g., NOVANTRONE®), non-steroidal antiinflammatory drugs (NSAIDs), analgesics, corticosteroids, and combinations thereof. In some embodiments, therapeutic agents can include compounds, drugs, and / or agents that can induce the generation of regulatory T cells (e.g., induced regulatory T cells). Non-limiting examples of such therapeutic agents include TGF-b, IL- 10, IL-2, and combinations thereof.

[0166] The pharmaceutical compounds described herein can include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any 33MEl\59465771.vl132301-11320undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.

[0167] A pharmaceutical composition described herein can also include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oilsoluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0168] Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions described herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0169] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms can be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0170] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable 34MEl\59465771.vl132301-11320solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions described herein is contemplated. A pharmaceutical composition can comprise a preservative or can be devoid of a preservative. Supplementary active compounds can be incorporated into the compositions.

[0171] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, the compositions can include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0172] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfdtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0173] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, from about 0.1 percent to about 70 percent, or from about 1 percent to about 30 percent of 35MEl\59465771.vl132301-11320active ingredient in combination with a pharmaceutically acceptable carrier.

[0174] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms described herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0175] In some embodiments, the anti-IL-7Ra antibody is administered at a flat dose (flat dose regimen).

[0176] In some embodiments, the anti-IL-7Ra antibody is administered at a dose based on body weight.

[0177] In some embodiments, the anti-IL-7Ra antibody is administered at a fixed dose with another antibody.

[0178] Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, bi-weekly (i.e., once every two weeks), monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient.

[0179] An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.

[0180] In some embodiments, the anti-IL-7Ra antibody, e.g., those described herein, is administered once a week.

[0181] In some embodiments, the anti-IL-7Ra antibody, e.g., those described herein, is administered once every two weeks.

[0182] In some embodiments, the treatment comprises 5-25 (e.g., 5, 6, 1, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) consecutive doses.36MEl\59465771.vl132301-11320

[0183] In some embodiments, the antibody is administered for a period of up to 10 weeks, 13 weeks, 26 weeks, 52 weeks, 2 years, 3 years, 5 years, 10 years, or lifetime / permanently. In some embodiments, the antibody is administered as needed when there is disease symptom.

[0184] In some methods, two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.

[0185] In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, or about 8 pg / mL.

[0186] In some methods, dosage is adjusted to achieve a plasma antibody concentration of > 5 pg / mL, > 6 pg / mL, > 7 pg / mL, or > 8 pg / mL.

[0187] An antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the halflife of the antibody in the patient. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a maintenance regime.

[0188] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions described herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.37MEl\59465771.vl132301-11320

[0189] A composition described herein can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. Routes of administration for the anti-IL-7R antibodies described herein can include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.

[0190] Alternatively, an antibody described herein could potentially be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0191] The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, poly orthoesters, and poly lactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art.

[0192] Therapeutic compositions can be administered with medical devices known in the art. For example, in a particular embodiment, a therapeutic composition described herein can be administered with a needleless hypodermic injection device. Examples of well-known implants and modules for use with anti-IL-7R antibodies described herein include an implantable micro-infusion pump for dispensing medication at a controlled rate; a therapeutic device for administering medicaments through the skin; a medication infusion pump for delivering medication at a precise infusion rate; a variable flow implantable infusion apparatus for continuous drug delivery; an osmotic drug delivery system having multichamber compartments; and an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known to those skilled in the art.38MEl\59465771.vl132301-11320Combination Therapy

[0193] In some embodiments, the method described herein comprises administering to the mammalian subject a second / additional therapeutic agent effective for treating the T-cell mediated inflammatory and / or an autoimmune disease.

[0194] In some embodiments, the second / additional therapeutic agent comprises a topical immunomodulator. In some embodiments, the topical immunomodulator comprises a calcineurin inhibitor. In some embodiments, the topical immunomodulator comprises a PDE-4 inhibitor. In some embodiments, the topical immunomodulator comprises a JAK inhibitor (such as tofacitinib, ruxolitinib, upadacitinib, abrocitinib, and baricitinib). In some embodiments, the topical immunomodulator comprises one or more of calcineurin inhibitor, PDE-4 inhibitor, and JAK inhibitor.

[0195] In some embodiments, the second / additional therapeutic agent comprises a systemic steroid, such as corticosteroid.

[0196] In some embodiments, the second / additional therapeutic agent comprises a topical corticosteroid.

[0197] In some embodiments, the second / additional therapeutic agent comprises tacrolimus and / or pimecrolimus.

[0198] In some embodiments, the second / additional therapeutic agent comprises phototherapy. In some embodiments, the phototherapy comprises narrow band ultraviolet B [NBUVB], In some embodiments, the phototherapy comprises ultraviolet B [UVB], In some embodiments, the phototherapy comprises ultraviolet Al [UVA1], In some embodiments, the phototherapy comprises psoralen and ultraviolet A [PUVA],

[0199] In some embodiments, the second / additional therapeutic agent comprises an allergen immunotherapy.

[0200] In some embodiments, the second / additional therapeutic agent comprises a leukotriene inhibitor.

[0201] In some embodiments, the second / additional therapeutic agent comprises an oral chemical synthetic immunomodulator. For example, the oral chemical synthetic immunomodulator may comprises one or more of: methotrexate, mycophenolate mofetil, interferon (IFN)-y, azathioprine, cyclosporine, a systemic biologic, a systemic targeted synthetic JAK inhibitor, a topical synthetic JAK inhibitor, or a PDE-4 inhibitor.

[0202] In some embodiments, the systemic biologic comprises one or more of dupliumab, ustekinumab, tralokinumab, and nemolizumab.39MEl\59465771.vl132301-11320

[0203] In some embodiments, the systemic targeted synthetic JAK inhibitor comprises one or more of tofacitinib, ruxolitinib, upadacitinib, abrocitinib, and / or baricitinib.

[0204] In some embodiments, the topical synthetic JAK inhibitor comprises delgocitinib.

[0205] In some embodiments, the PDE-4 inhibitor comprises crisaborole.

[0206] With the general aspects and embodiments described above, the following illustrative (non-limiting) example is provided to further demonstrates specific embodiments.EXAMPLESExample 1: Use of COMPOUND A for the Treatment of Eosinophilic granulomatosis with poly angiitis (EGPA)

[0207] This example demonstrates that the anti-IL7Ra antibody COMPOUND A is effective to treat EGPA in patients in need thereof.

[0208] The primary objective is to show the efficacy of COMPOUND A vs placebo after the commencement of the treatment, in participants with EGPA. This primary objective is assessed based on the primary endpoint of percentage of patients with EGPA (such as ones with relapsing or refractory EGPA), achieving remission after 52 weeks of treatment, defined as BVAS = 0 and OCS dose < 4 mg / day (main remission definition) at both Weeks 36 and 48, for COMPOUND A vs placebo.

[0209] A supportive endpoint may also be included, defined as proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS = 0 and OCS dose < 7.5 mg / day (supportive remission definition) at both Weeks 36 and 48.

[0210] A secondary objective of the trial is to show the efficacy of COMPOUND A vs placebo on treating EGPA through 52 weeks of treatment in participants with EGPA. This secondary objective is assessed through analyzing a number of secondary endpoints, including:• Total accrued duration of remission for the following categories: 0 week, > 0 to < 12 week, 12 to < 24 week, 24 to < 36 week, > 36 week.• Total accrued duration of sustained remission for the following categories: 0 week, > 0 to < 12 week, 12 to < 24 week, 24 to < 36 week, > 36 week.• Time from randomization to first Eosinophilic Granulomatosis with Polyangiitis (EGPA) relapse, where relapse is defined as any of the following:- Active vasculitis (BVAS > 0); OR40MEl\59465771.vl132301-11320- Active asthma symptoms and / or signs with a corresponding worsening in ACQ-6 score; OR- Active nasal and / or sinus disease, with a corresponding worsening in at least one of the sino-nasal symptom questions; warranting any of the following:- An increased dose of OCS therapy to > 4 mg / day prednisolone total daily dose; OR - An increased dose or addition of immunosuppressive therapy; OR- Hospitalization related to EGPA worsening Calculated using the Kaplan-Meier technique.• Annualized Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse Rate • Average Daily Dose of Prednisolone / Prednisone and Change From Baseline During Week 48 Through 52

[0211] Patients receiving treatment (e.g., baseline COMPOUND A group) are expected to have statistically significant improvement over matched placebo control (e.g., patients receiving placebo), and with demonstrated non-inferiority over the standard of care antibody drug mepolizumab.Example 2: Use of COMPOUND A for the Treatment of Eosinophilic esophagitis (EoE)

[0212] The study is designed as a placebo controlled trial to assess the preliminary efficacy, safety, tolerability, PK, and PD of COMPOUND A in in adult subjects with EoE. COMPOUND A or matching placebo is administered subcutaneously in the clinic setting post-randomization.

[0213] The primary objectives of the study may include:• To determine the treatment effect of COMPOUND A compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures• To assess the safety and efficacy of COMPOUND A treatment in adult and adolescent patients with EoE after up to 52 weeks of treatment as assessed by histological and clinical measures.

[0214] Some secondary objectives of the study may include:• To evaluate the safety, tolerability, and immunogenicity of COMPOUND A treatment for up to 52 weeks in adult and adolescent patients with EoE• To explore the relationship between COMPOUND A concentration and responses in adult and adolescent patients with EoE, using descriptive analyses41MEl\59465771.vl132301-11320• To evaluate the effects of COMPOUND A on tran scrip tomic signatures associated with EoE and type 2 inflammation• To demonstrate the efficacy of COMPOUND A treatment compared to placebo after 24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who have previously received swallowed topical corticosteroids

[0215] Key Inclusion Criteria may include:• A documented diagnosis of EoE by endoscopic biopsy• Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial eosinophilic infiltration• History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of solids) per week in the 4 weeks prior to screening

[0216] Primary outcome measures may include:• Percentage of participants achieving peak esophageal intraepithelial eosinophil count of <6 eosinophils per high-power field (Eos / Hpf) in all three regions at week 24. Esophageal intraepithelial eosinophil count is obtained by esophageal endoscopy with biopsies (all 3 esophageal regions: proximal, mid, and distal).• Absolute change from baseline in dysphagia symptom questionnaire (DSQ) total score at week 24. The DSQ is used to measure the frequency and intensity of dysphagia. DSQ scores can range from 0 to 84, with a lower score indicating less- frequent or less- severe dysphagia.

[0217] Secondary outcome measures may include:• Percentage of participants achieving peak esophageal intraepithelial eosinophil count (Eos / Hpf) in all three regions at week 24.• Percent Change From Baseline in DSQ Total Score at Week 24• Absolute Change From Baseline in Eosinophilic Esophagitis Histology Scoring System (EoEHSS) Mean Grade Score at Week 24• NES for the Relative Change From Baseline in the Type 2 Inflammation Signature (T2INF) at Week 24• Concentration of Functional COMPOUND A in Serum at Week 52• Incidence of Treatment-emergent Anti-drug Antibody (ADA) Response42MEl\59465771.vl132301-11320Example 3: Use of COMPOUND A for the Treatment of Chronic rhinosinusitis with nasal polyps ( CRSwNP)

[0218] The study is designed as a placebo controlled trial to assess the preliminary efficacy, safety, tolerability, PK, and PD of COMPOUND A in in adult subjects with CRSwNP.

[0219] The primary objective of the study may be to evaluate the effect of COMPOUND A on the nasal congestion score (NCS). Nasal congestion is scored from 0 (“No symptoms”) to 3 (“Severe symptoms”). Higher scores denote greater symptom severity. Changes from baseline in NCS is measured at 1, 3 and 6 months, and 1, 1.5, 2 and 3 years for the commencement of treatment.

[0220] Selected secondary objectives may include one or more of:• To evaluate the effect of COMPOUND A on the nasal polyp score (NPS).• To evaluate the effect of COMPOUND A on the Visual analogue scale (VAS).• To evaluate the effect of COMPOUND A on the Sino-Nasal Outcome Test-22 items (SNOT-22).• To compare the effect of COMPOUND A on the asthma control questionnaires 5-item version(ACQ-5).• To compare the effect of COMPOUND A on the asthma quality of life questionnaire (AQLQ).• To compare the effect of COMPOUND A on the sense of smell with the short questionnaire of olfactory disorders: negative statements (sQOD-NS).Example 4: Use of COMPOUND A for the Treatment ofHS (hidradenitis suppurativa)

[0221] The study is designed as a placebo controlled trial to assess the preliminary efficacy, safety, tolerability, PK, and PD of COMPOUND A in in adult subjects with HS.

[0222] The purpose of this study is to demonstrate superiority of COMPOUND A at Week 16, based on Hidradenitis Suppurativa Clinical Response (HiSCR) rates versus placebo, along with the maintenance of efficacy of COMPOUND A at Week 52 in subjects with moderate to severe HS.

[0223] Key inclusion criteria may include:• Subject has moderate-to- severe HS as defined by: 1. HS lesions in at least 2 distinct anatomic areas, one of which is Hurley stage II or III on evaluation at Screening. 2.43MEl\59465771.vl132301-11320Stable HS for at least 2 months (60 days) prior to Screening and also at the Baseline visit as determined by the investigator.• Total abscess and inflammatory nodule (AN) count of greater than or equal to 3 at the Baseline visit.• Subject has had HS diagnosis for at least 3 months prior to Baseline.

[0224] Primary outcome measures may include:• Percentage of Participants With Hidradenitis Suppurativa Clinical Response (HiSCR50): HiSCR50 at Week 16 is defined as at least a 50% decrease in Abscess and inflammatory Nodule (AN) count compared to baseline with no increase in the number of abscesses and / or in the number of draining fistulas from baseline to Week 16. The baseline is defined as the last assessment (including unscheduled visits) obtained before / on the day of the first administration of the study treatment, or on the randomization date if there had been no drug administration.

[0225] Secondary outcome measures may include:• Percentage Change From Baseline in AN Count: Percent change from baseline in abscesses and inflammatory nodules (AN) count.• Percentage of Participants With Hidradenitis Suppurativa (HS) Flares: Percentage of participants who experience at least one flare over 16 weeks. A flare is defined as at least a 25% increase in abscesses and inflammatory nodules (AN) count with a minimum increase of 2 AN relative to baseline.• Percentage of Participants Achieving NRS30: Patients achieving Numerical Rating Scale score of 30 (NRS30) at week 16, defined as at least a 30% reduction and at least one unit reduction from baseline in the Patient's Global assessment of Skin Pain (where range 0 [no skin pain] to 10 [worst skin pain]).Example 5: Use of COMPOUND A for the Treatment of Celiac Disease

[0226] The study is designed as a placebo controlled trial to assess the preliminary efficacy, safety, tolerability, PK, and PD of COMPOUND A in in adult subjects with celwith non-responsive celiac disease (NRCD) who are on a gluten-free diet (GFD).

[0227] Key Inclusion Criteria may include:• A diagnosis of celiac disease by intestinal biopsy• Following a GFD for at least 12 consecutive months44MEl\59465771.vl132301-11320• Must have detectable (above the lower limit of detection) serum celiac-related antibodies• Must have human leukocyte antigen DQ (HLA-DQ) typing consistent with celiac disease (DQ2 and / or DQ8)

[0228] Primary outcome measures may include:• Efficacy of COMPOUND A in attenuating the symptoms of celiac disease in adult patients with NRCD as measured by the Celiac Disease Patient-Reported Outcome (CeD PRO) questionnaire: Celiac Disease Patient-Reported Outcome (CeD PRO) at 24 weeks

[0229] Secondary outcome measures may include:• Effect of treatment with COMPOUND A on other measures of disease activity:Intraepithelial lymphocyte (IEL) density at 24 weeks• Incidence of treatment-emergent adverse events (TEAEs): Safety endpoint at 28 weeks• Serum trough concentrations of COMPOUND A at scheduled visits: Characterize the pharmacokinetics (PK) of COMPOUND A at 28 weeks• Incidence of anti-COMPOUND A antibodies: Immunogenicity endpoint at 28 weeksExample 6: Preliminary Results

[0230] 200 mg COMPOUND A was administered as a single 2-mL subcutaneous injection every 2 weeks (Q2W) to confirm median steady-state serum trough concentration of COMPOUND A. The dose was based on:• • preliminary data demonstrating acceptable clinical safety of COMPOUND A in disease subjects following doses up to 3 mg / kg administered Q2W.• • Flat dosing of 200 mg is predicted to achieve concentrations similar to and within the range of exposures achieved following 3 mg / kg SC administered Q2W.• • Preliminary population PK simulations project that a dose of 200 mg administered Q2W will result in a median steady-state serum trough concentration of 20.0 pg / mL and the majority of subjects maintaining concentrations >5 pg / mL throughout dosing.45MEl\59465771.vl132301-11320Example 7: Binding properties of COMPOUND ASPR analysis of binding to FcyR by a COMPOUND A precursor

[0231] Fey receptors are found on hematopoietic cells and mediate antibody-antigen-induced effector functions. These include antibody-dependent cell-mediated cytotoxicity and antibody dependent cellular phagocytosis. The binding of specific non-variable regions of IgGl with FcyRs expressed on immune cells mediates effector functions of the antigenantibody complexes.

[0232] The precursor of COMPOUND A (ClGM / 2hIgGl) was tested for its binding to human and monkey Fey receptors (types I, II, and III) by surface plasma resonance (SPR). The FcyRs screened included FcyRI (hCD64 and cynoCD64), FcyRII (hCD32a-H131 and hCD32a-R131, hCD32b, cynoCD32a, and cynoCD32b), and FcyRIII (hCD16a-V158, hCD16b-NA2, and cynoCD16) subtypes. The ClGM / 2hIgGl antibody demonstrated the expected binding profiles for human and cynomolgus monkey FcyRI, FcyRII and FcyRIII (data not shown)Lack of binding by COMPOUND A to cynomolgus monkey and human Fey receptors

[0233] Three amino acid substitutions were engineered into the Fc chain of the precursor CICM / 2hGl to attenuate effector function, arriving at COMPOUND A. The mutations included a leucine to alanine substitution at position 234 (L234A), a leucine to glutamic acid substitution at position 235 (L235E), and a glycine to alanine substitution at position 237 (G237A). COMPOUND A was expressed in HEK293 and CHO cells.

[0234] COMPOUND A (1 pM) was purified from cell supernatants and assessed for binding to human and cynomolgus monkey FcyRs by SPR. The FcyRs screened included FcyRI (hCD64 and cynoCD64), FcyRII (hCD32a-H131, hCD32a-R131, hCD32b, cynoCD32a, and cynoCD32b), and FcyRIII (hCD16a-V158, hCD16b-NA2, and cynoCD16) subtypes.

[0235] The binding of COMPOUND A to all FcyRs was below detectable limits when tested at a high concentration (1 pM) (data not shown). In contrast, an IgGl -positive control antibody showed the expected high degree of binding to human FcyRI, with moderate binding to both FcyRII and FcyRIII (data not shown).

[0236] Taken together, these data confirm that the combined L234A, L235E, and G237A substitutions engineered into the Fc domain of COMPOUND A effectively minimize potential effector function.46MEl\59465771.vl132301-11320Lack of binding by COMPOUND A to Clq

[0237] Clq binding to the Fc domain of IgGl antibodies can mediate complement-mediated cell lysis. The ability of COMPOUND A to bind Clq was evaluated using an ELISA assay. Briefly, microtiter plates were coated with human IL-7Ra, and COMPOUND A from 2 different lots were added at varying concentrations to the coated plates, followed by a saturating concentration of Clq purified from human serum. Bound Clq was detected with a sheep anti-human Clq antibody. Positive control included human IgGl. Positive control IgGl showed the expected affinity for Clq; however, neither lot of COMPOUND A showed any measurable binding to Clq at concentrations of up to 1000 ng / mL (6.7 nM).

[0238] This data shows that COMPOUND A can evade Clq-mediated complement-mediated cell lysis when administered to human.Binding properties of COMPOUND A to human and cynomolgus monkey FcRn at pH 6.0 and 7.4

[0239] Neonatal Fc receptor (FcRn), expressed on endothelial and bone marrow-derived cells, extends the half-life of IgGs by facilitating their transport out of epithelial cell endosomes (pH 6.0) where they would otherwise be degraded, and back into the bloodstream as functional immunoglobulins (pH 7.4). Endosomal recycling is facilitated by a pH shift (tight binding at pH 6.0 and low binding / high dissociation at pH 7.4) in the IgG-FcRn interaction.

[0240] The binding of COMPOUND A to a panel of human and cynomolgus neonatal Fc receptors (hFcRn and cFcRn, respectively) were assessed using a single cycle Biacore analysis. The Kd of COMPOUND A binding to human and cynomolgus monkey FcRn was 686 and 866 nM, respectively, at pH 6.0. COMPOUND A did not bind to FcRn from either human or monkey at pH 7.4. This pH-dependent shift in antigen affinity facilitates the release of complexed COMPOUND A in lysosome from lysosomal degradation. Irrelevant human IgGl and IgG4 wild-type antibodies were run as controls.

[0241] These findings suggest that endosomal recycling is expected to enhance the biostability / half-life of COMPOUND A in vivo.SPR analysis of binding to human and cynomolgus IL-7Ra at pH 6.0 and 7.4

[0242] COMPOUND A was evaluated for binding to purified recombinant human and cynomolgus monkey IL-7Ra via SPR. The Kd of COMPOUND A for human IL-7Ra is 1.3 nM and for cynomolgus monkey IL-7Ra is 1.7 nM at pH 7.4. The binding affinity of47MEl\59465771.vl132301-11320COMPOUND A for both human and cynomolgus monkey IL-7Ra was 4-fold weaker at pH 6.0, with Kd values of 5.3 nM for human IL-7Ra (hIL-7Ra), and 7.0 nM for cynomolgus monkey IL-7Ra (cIL-7Ra ) (see Table 2 below).Table 2: Binding Affinity of COMPOUND A to Human and Cynomolgus Monkey IL- 7RaKd: receptor binding affinity dissociation constant; SPR: surface plasmon resonance.

[0243] These data demonstrate that COMPOUND A bound with equivalent high affinity to human and cynomolgus monkey IL-7Ra at pH 6.0 and 7.4. For both species the binding affinity was roughly 4-fold higher at pH 7.4 compared with pH 6.0. This pH-dependent shift in antigen affinity may further facilitate the release of complexed COMPOUND A from the lysosomal to avoid lysosomal degradation of COMPOUND A.Example 8: In vitro assessment of efficacies of COMPOUND AReceptor Occupancy and Inhibition of IL-7 Stimulated Phosphorylation ofSTAT5 (pSTAT5) in CD4 T Cells From Healthy Volunteers

[0244] The effect of COMPOUND A on IL-7-induced pSTAT5 expression was evaluated in CD4+T cells in healthy human volunteers (n = 3). Anticoagulated whole blood from healthy volunteers was incubated with increasing concentrations of COMPOUND A in the presence of recombinant human IL-7 (10 ng / mL). The percentage of pSTAT5 in CD4+T cells was measured by flow cytometry using fluorescent probes for CD3+, CD4+, CD45RA+, and pSTAT5.

[0245] COMPOUND A showed potent inhibition of pSTAT5 on naive CD4+T cells from all 3 healthy volunteers (n = 3) with mean IC50 values of 0.16 to 0.27 nM (23.7 to 40.4 ng / mL, respectively).Inhibition ofpSTAT5 in Naive CD4+ and CD8 T-Cells From Healthy Volunteers

[0246] COMPOUND A was evaluated for target engagement and inhibition of IL-7 induced IL-7R signaling on human T cells from normal healthy volunteers. Freshly drawn48MEl\59465771.vl132301-11320blood was incubated ex vivo with IL-7 (100 ng / mL) for 15 minutes, and pSTAT5 levels were measured by flow cytometry.

[0247] As shown in Table 3, COMPOUND A potently inhibited IL-7-induced phosphorylation of STAT5 in naive (CD45RA+) and memory (CD45RA ) T cells (both CD4 and CD8 phenotypes) from normal healthy volunteers with IC50 values ranging between 0.38 and 0.54 nM (equivalent to about 57 to 81 ng / mL).Table 3: Inhibition of IL-7-Induced pSTAT5 in T Cells by COMPOUND A (ICso in nM)Abbreviations: IC50: half maximal inhibitory concentration; NHV: normal healthy volunteers; CD45RO: marker of naive CD3+ T cells.aIC50 values were calculated only when CD8 T cells responded to IL-7.COMPOUND A is an IL-7R antagonist antibody with no partial agonist activity

[0248] To determine if COMPOUND A had any partial agonist capabilities, whole blood or purified peripheral blood monocyte cells (PBMCs) were collected from healthy volunteers (n = 3). COMPOUND A was incubated in each matrix at 8 concentrations ranging from 1 to 100 nM. Signal transduction was assessed by AlphaLISA® SureFire®Ultra™ pSTAT5 to detect pSTAT5. Negative control used a non-targeting IgG isotype, and the positive control was IL-7 (2 nM). IL-7 increased pSTAT5 levels by an average of 4.7-fold (±1.6) and 21.1-fold (±2.8) in whole blood and PBMCs, respectively. No significant induction of pSTAT5 was observed at any concentration of COMPOUND A (1, 2, 3, 6, 13, 25, 50, or 100 nM) in either whole blood or PBMCs, demonstrating that COMPOUND A is a full antagonist at the IL-7R with no partial agonist activity. These data are presented in Tab 4.Table 4. COMPOUND A is an Antagonist With no Intrinsic Partial Agonist Activity49MEl\59465771.vl132301-11320COMPOUND A Inhibits TSLP-lnduced TARC Production by PBMCs

[0249] Thymus-activated regulated chemokine (TARC, also known as CCL17) is an important chemokine released from monocytes and dendritic cells in response to thymic stromal lymphopoietin (TSLP) stimulation. TARC drives the maturation of dendritic cells and their production of IL-23 as well as the proliferation of CD4+T cells. TSLP is highly expressed in atopic dermatitis (AD) skin lesions. Signaling through IL-7Ra / TLSPR and IL-7Ra / CD132 has been demonstrated to produce additive inflammatory effects.

[0250] COMPOUND A binds to the IL-7Ra subunit that is common to both the IL-7 receptor (IL-7Ra / CD132) and the TSLP receptor complex (IL-7Ra / TSLPR). COMPOUND A inhibited TSLP-induced production of TARC from PBMCs enriched for monocytes (3 independent assays with 1-2 donors) with an average IC50 of 2.9 nM (428 ng / mL).

[0251] Thus, in addition to blocking IL-7-induced signaling, COMPOUND A also inhibits TSLP induced signaling at low nM concentrations.Example 9: Assessment of efficacies of COMPOUND A in humanized mouse model Efficacy of COMPOUND A in a Humanized Mouse Graft versus Host Disease Model

[0252] Graft-versus-host disease (GvHD) is a systemic disease, and skin is often one of the target organs.

[0253] COMPOUND A was evaluated with prophylactic treatment in a humanized non-obese diabetic severe combined immune deficiency-mice with a humanized immune system 50MEl\59465771.vl132301-11320(NOD-SCID-IL ry"111[Hu-NSG]) mouse model of GvHD. NSG mice are immunodeficient due to the lack of mature murine lymphocytes and natural killer (NK) cells, which allows human peripheral blood mononuclear cells (PBMCs) to engraft with high efficiency. NSG mice were injected intravenously (IV) with human PBMCs that engrafted and led to the development of a robust xenogeneic-GvHD response, reproducing many aspects of the human disease.

[0254] A reference IL-7Ra antagonist antibody (A3312F, which epitope residues appear to include all epitope residues of COMPOUND A) was evaluated in 2 treatment regimens (prophylactic and therapeutic modes), and the data from the prophylactic regimen was presented herein, with A3312F serving as a positive control for COMPOUND A in this model of GvHD.

[0255] In the prophylactic treatment study, COMPOUND A, administered subcutaneously twice weekly (5 mg / kg) for 3 weeks starting on Day (-1) (the day before adoptive PBMC transfer) to NSG mice (n = 7 females), showed robust inhibition of GvHD as demonstrated by a reduction in body weight loss, inflammatory cytokine expression, and immune cell proliferation (see FIGs. 1A-1C). A3312F, tested in the same study, showed comparable efficacy to COMPOUND A.

[0256] In a separate experiment, target engagement was assessed by evaluating the level of pSTAT5 in cells from whole blood and spleens. COMPOUND A treatment (0.2, 1, or 5 mg / kg 2x / week SC) was initiated 5 days after human PBMC transfer to NSG mice. Whole blood and spleens were collected 72 and 120 hours, respectively, after the fourth dose of COMPOUND A. Cells were collected and stimulated with human IL-7 for 15 minutes, and pSTAT5 levels were analyzed in human CD4+and CD8+T cells by flow cytometry.COMPOUND A demonstrated complete target engagement and inhibition of IL-7-induced pSTAT5 at 1 and 5 mg / kg treatments (see FIG. 2A-2B). This confirms that inhibition of IL-7Ra signaling with COMPOUND A is protective in a humanized mouse model of GvHD and that complete target engagement can be achieved.

[0257] In several related experiments, a mouse surrogate antibody (SB 14) was used to further assess the role of IL-7Ra inhibition to treat other disease indications in mouse models of such disease indications (COMPOUND A was not used in these experiments partly because COMPOUND A does not cross-react with the mouse IL-7Ra (data not shown)). Collectively, these additional in vivo studies demonstrated that short-term inhibition of IL-7Ra signaling provides a durable, efficacious response, and suggested the potential for an51MEl\59465771.vl132301-11320infrequent dosing paradigm to sustain clinical efficacy. Furthermore, it demonstrated the importance of IL-7R signaling in driving T cell-mediated disease processes.

[0258] Interestingly, in at least one such disease model, a different inhibitor of T cell activation, CTLA4-Ig, did not exhibit efficacy in that disease model using the same treatment strategy (data not shown), thus demonstrating a clear differentiation between anti-IL-7Ra mAb and CTLA4-Ig treatment, and highlighting the potential for a durable, drug-free response with IL-7Ra mAb treatment.Example 10: Pharmacokinetics / Pharmacodynamics (PK / PD) in Cynomolgus Monkeys Single-dose intravenous pharmacokinetics and pharmacodynamics

[0259] This study was conducted to compare the PK and PD profiles of low doses of COMPOUND A with a reference positive control IL-7Ra antagonist antibody (A3312F) when administered to cynomolgus monkeys, and to provide data to support the use of COMPOUND A in humans. COMPOUND A and A3312F were administered by IV injection at doses of 0 (vehicle), 0.1 (low dose), 0.5 (mid dose), or 3.0 (high dose) mg / kg to groups of 1 or 2 monkeys per sex. All doses were administered at 1 mL / kg in a vehicle / carrier consisting of 20 mM histidine, 260 mM sucrose, 0.05 mM diethylenetriaminepentaacetic acid (DTPA), and 0.05% Tween 80, pH 6.0.

[0260] Criteria for PD evaluation included total and soluble IL-7R levels in blood and plasma, inhibition of IL-7-induced pSTAT5, receptor occupancy (RO), and peripheral lymphocyte phenotyping. Pharmacokinetic endpoints included AUC, Cmax, and Tmax and immunogenicity endpoint included anti-drug antibody (ADA).

[0261] On Day 1, 100% RO was achieved at 4 hours after dosing and maintained on Days 2-4 at all doses for both COMPOUND A and A3312F. The vehicle control group consistently exhibited no RO for the duration of the study. RO decreased for the remainder of the study, starting with the low dose of A3312F falling below 95% RO on Day 4, while the other drug-treated groups maintained 100% RO. On Day 7, the RO of both low dose groups fell below 50%. On Day 10, the RO of low dose of A3312F returned to vehicle control levels, the mid dose below 50% and the high dose below 90%. The low dose of COMPOUND A also returned to vehicle control, while the mid dose averaged below 50% (with variability), and the high dose remained at 100% RO. On Day 14, all A3312F dose groups returned to vehicle control levels (no RO), whereas the COMPOUND A low and mid doses both returned to52MEl\59465771.vl132301-11320vehicle levels but the high dose of COMPOUND A maintained >50% RO. All doses for both COMPOUND A and A3312F were comparable to vehicle control levels by Day 17.

[0262] Cynomolgus monkey IL-7-induced pSTAT5 was strongly inhibited by both COMPOUND A and A3312F. The low dose of 0.1 mg / kg showed notable inhibition of pSTAT5 (>80%) at early time points (Days 1-3) with COMPOUND A being slightly more effective than A3312F. The intermediate dose of 0.5 mg / kg COMPOUND A was more effective than A3312F at maintaining complete inhibition of pSTAT5 through Day 5, with an approximate 4-fold higher suppression on Day 5. At the high dose of 3 mg / kg, complete inhibition of pSTAT5 activity was sustained through Day 8 with COMPOUND A treatment, while A3312F treatment demonstrated lesser inhibition of pSTAT5 over the same time period. Moreover, COMPOUND A at Day 11 continued to substantially inhibit IL-7 induced pSTAT5 while A3312F exhibited a complete loss of this inhibitory activity.

[0263] Both mean total (blood) and soluble (plasma) IL-7R concentrations, which encompass both free and bound IL-7R, increased after administration of COMPOUND A and maximum levels were generally reached by 8 to 11 days. Mean soluble (plasma) IL-7R concentrations increased to a greater extent compared to total (blood) IL-7R levels. The cell surface IL-7R levels measured using flow cytometry did not significantly change after COMPOUND A or A3312F administration, suggesting that decreased elimination of soluble IL-7R- COMPOUND A complexes is the cause for increase in total IL-7R levels in blood.

[0264] On Day 8, there was a trend of reduction in peripheral lymphocytes as compared to baseline in both COMPOUND A and A3312F treated animals, which was most prominent at the highest dose (3 mg / kg). However, no overt differences in peripheral lymphocyte subsets were observed for either COMPOUND A or A3312F during the study. There was variability in lymphocyte populations among animals in the same group, however, suggesting that the variability may be due to stress (z.e., handling of the monkeys, etc.) and the study’s small sample size per dose group (n = 3).

[0265] COMPOUND A exposure was evaluated after single IV doses of <3 mg / kg and compared to A3312F. Mean exposures (AUCs) at 3 mg / kg in the first week, before anti-drug antibody (ADA) formation, were higher for COMPOUND A compared to A3312F with a mean AUC from 0 extrapolated to infinity (AUCinf) <287 pg*day / mL and AUCinf <135 pg*day / mL, respectively) (see Table 5). ADA formation was accompanied by concomitant accelerated decline of serum concentrations, RO, and inhibition of pSTAT5 for COMPOUND A and A3312F.53MEl\59465771.vl132301-11320Table 5. Mean Serum COMPOUND A and A3312F Pharmacokinetic ParametersAbbreviations: AUCmf: area under the concentration-time curve from 0 extrapolated to infinity; Cmax: maximum plasma concentration; CL: clearance; IV: intravenous; PK: pharmacokinetic; Tm: time of maximum plasma concentration.

[0266] ADAs were detected in all monkeys dosed with COMPOUND A. ADAs were detected in 3, 3, and 2 of 3 monkeys dosed with A3312F at 0.1, 0.5, and 3 mg / kg, respectively, by Day 11. The presence of ADAs led to generally lower serum COMPOUND A and A3312F concentrations and lower individual COMPOUND A and A3312F systemic exposures on and after Day 11 (240 hours post dose) in all monkeys.

[0267] In summary, COMPOUND A and A3312F were well tolerated by monkeys after single IV doses of up to 3 mg / kg. There were no drug-related clinical observations or effects on body weight observed during the study. Good correlation was observed between the inhibition pSTAT5 in the CD4+CD45RA+ T cell population and serum concentration of antihuman IL-7R antibodies. More than 95% RO resulted in 90% inhibition of pSTAT5. The inhibition of pSTAT5 levels, a proximal biomarker of IL-7R signaling, by COMPOUND A was similar but more prolonged than that by A3312F and suggests that COMPOUND A exhibits improved PK, but similar in vivo potency compared to A3312F. No significant change in lymphocyte phenotypes was observed for either COMPOUND A or A3312F after a single-dose administration. Despite the impact of ADAs on COMPOUND A’s concentration, meaningful exposure and evaluation of toxicological endpoints were achieved.Single-dose subcutaneous pharmacokinetics and pharmacodynamics

[0268] Systemic toxicokinetic profile, tolerability, RO, and PD changes as a measure of target engagement, assess immune responses was determined for subcutaneous (SC) administration of COMPOUND A at doses of 0 (vehicle), 3, and 30 mg / kg to groups of 2 male and 2 female cynomolgus monkeys. Criteria for PD evaluation included assessments of IL-7-induced pSTAT5, IL-7 RO, peripheral blood lymphocyte phenotyping (T cell, B cell, and NK cell [T / B / NK]), T cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) immunization, and total and soluble IL-7R levels.54MEl\59465771.vl132301-11320

[0269] In the 3 mg / kg SC dose group, the RO was 100% through Day 8, 98% on Day 11, 16% on Day 15, 12% on Day 22, and below the limit of quantitation (BLQ) on Day 36. In the 30 mg / kg SC dose group, RO was 100% through Day 11, 70% on Day 15, and BLQ on Day 22.

[0270] Inhibition of IL-7-induced pSTAT5 on CD3+ T cells was observed in all dose groups, 4 hours post dose (between 92% and 99% mean inhibition), indicating significant PD activity. In the 3 mg / kg SC group, the mean % pSTAT5 levels were 100% through Day 8, 79% on Day 11, and returned to baseline levels on Day 22. In the 30 mg / kg SC dose group the % pSTAT5 inhibition was 100% through Day 11, 30% on Day 15, and returned to baseline on Day 22. Inhibition of pSTAT5 generally correlated with the degree of IL-7 RO and systemic exposure of COMPOUND A that was decreased due to the presence of ADAs in all monkeys by Day 11.

[0271] Mean exposures (AUCo-336h and Cmax) generally increased approximately dose-proportionally by SC injection between 3 and 30 mg / kg. No substantial sex differences were noted. The systemic exposure after a single SC dose of 3 mg / kg was comparable to that after a single IV dose of 3 mg / kg, and the bioavailability was 78% by calculating with the first week data.

[0272] Overall, COMPOUND A was well tolerated by monkeys after a single SC dose <30 mg / kg (AUCo-336h <61,314 pg*h / mL). COMPOUND A-related PD activity was noted at all doses, as demonstrated by inhibition of IL-7-induced pSTAT5, and generally correlated with IL-7 RO and COMPOUND A exposure, which was decreased due to the presence of ADAs in all monkeys by Day 11. Decreased lymphocyte subpopulations observed as early as on Day 8 was consistent with hematology findings of decreased lymphocytes (at >3 mg / kg SC). Despite the impact of ADAs on COMPOUND A’s concentration, meaningful exposure and evaluation of toxicological endpoints were achieved.Six-week intermittent-dose (QW) SC toxicity study with an 8-week recovery period

[0273] COMPOUND A was administered SC once weekly at doses of 0 (vehicle), 2, 10, or 50 mg / kg to groups of 5 monkeys per sex. Scheduled necropsies were conducted after 6 weeks of dosing (7 doses) (3 / sex / group) and after an 8-week recovery period (2 / sex / group).

[0274] At all doses near-complete (>95%) inhibition of IL-7 induced pSTAT5 on CD3+ T cells (PD activity) and near-complete (>98%) IL-7 RO on CD3+ T cells (target engagement) were observed at 4 hours post dose on Day 1 through Day 8. Recovery of pSTAT5 and loss of IL-7 RO were noted on Day 22 and correlated with decreased systemic exposures to COMPOUND A due to the presence of higher levels of ADAs. Overall, target 55MEl\59465771.vl132301-11320engagement and PD activity correlated with sustained systemic exposures in monkeys with minimal or no ADA responses.

[0275] At all doses, there were decreases in total T (as low as 0.5 lx relative to vehicle control group mean), helper T (CD4+, as low as 0.5 lx), and cytotoxic T (CD8+, as low as 0.48x) cells on Day 8 consistent with the hematology findings of a decrease in total lymphocyte counts on Day 8, but no decrease in B and NK cells. Due to reduced systemic exposures of COMPOUND A as a result of ADA, T cell subset counts returned to baseline levels by Day 22 with the exception of the highest dose group of 50 mg / kg in which drug levels remained in circulation. In the 50 mg / kg dose group, the decreases in T cell subsets were maintained through the end of the recovery period (Day 97 / 99) and consistent with drug maintained in circulation.

[0276] After doses up to 50 mg / kg, there were no COMPOUND A-related changes in qualitative and quantitative electrocardiographic evaluations. Additional examinations demonstrated no COMPOUND A-related changes in neurological endpoints, respiratory rates, body temperatures, evaluations of lung sounds and mucus membrane color, and arterial oxygen saturation determinations.

[0277] Overall, COMPOUND A was well tolerated by monkeys for 6 weeks at SC, once weekly doses of 2, 10, or 50 mg / kg. SC toxikinetic profile was approximately doseproportional on Day 1 across the dose range tested but was later affected by the development of ADA in most animals. High-dose animals maintained exposure, albeit variable, allowing for meaningful interpretation of toxicological endpoints and the definition of a NOAEL. At all doses, PD activity (inhibition of IL-7 induced pSTAT5) generally correlated with IL-7 RO (target engagement) and COMPOUND A exposure and was decreased due to high levels of ADAs (more prominently at the lower doses).Three-month repeat dose toxicity study of COMPOUND A by subcutaneous injection with a 6-month recovery period

[0278] COMPOUND A was administered SC once weekly at doses of 0 (vehicle), 10, 50, and 150 mg / kg to groups of 5 monkeys per sex.

[0279] During Week 1 of the ECG evaluations, 7 ventricular premature complexes (VPCs) were observed in 1 male monkey over a 10-second interval in the high dose group (150 mg / kg QW). The relationship of the VPCs to COMPOUND A is unclear for the following reasons: VPCs were observed in only 1 of 30 animals in this study; and VPCs can be an incidental finding in naive cynomolgus monkeys (~8% of animals with 1 minute ECGs performed 2 weeks apart) as well as spontaneous incidence over time can be quite variable 56MEl\59465771.vl132301-11320and their occurrence sporadic when evaluated over 24 hours. Additionally, there were no histologic correlations or QT / QTc interval changes to predispose this animal to ventricular arrhythmias. The presence of VPCs in this animal was not associated with any clinical signs and hence the arrhythmia was not considered adverse.

[0280] Overall, administration of COMPOUND A to cynomolgus monkeys, administered by weekly subcutaneous injection for 3 months was well tolerated at doses of 10, 50, and 150 mg / kg. Greater than 95% RO was maintained at 50 mg / kg (7 / 10 animals) and at 150 mg / kg (10 / 10 animals) through the 3-month dosing phase. Loss of >95% RO at 10 mg / kg (9 / 10 animals) and 50 mg / kg (3 / 10 animals) was observed on Day 29 or Day 57 and correlated with detectable ADA. A decline in CD4+ and CD8+ T cell populations were observed, with the largest impact on naive and CM T-cells at doses of COMPOUND A >50 mg / kg. These reductions are related to the pharmacological effects of COMPOUND A and were generally correlated with observed RO. Total T lymphocyte counts, T cell subsets and B cells were partially or completely recovered to baseline in the males, but decreases in T lymphocyte counts, T cell subsets and B cells were maintained with minimal or no recovery in female monkeys, which are generally correlated with observed durability of RO. There were no histological correlations with the decreased lymphocytes at end of the recovery phase.

[0281] Exposure of COMPOUND A was maintained >60,800 pg*h / mL through the dosing phase in 7 / 10 animals at 50 mg / kg and 10 / 10 animals at 150 mg / kg despite detectable ADA. Based on the non-adverse nature of the COMPOUND A-related pathology changes at the end of the dosing period, the no-observed-adverse-effect level (NOAEL) was considered to be 150 mg / kg, the highest dose tested. At the phase NOAEL, the mean Cmax and AUC sex combined values were 3570 pg / mL and 314,000 pg*h / mL, respectively.Six-month study of COMPOUND A by subcutaneous injection in sexually mature and not sexually mature cynomolgus monkeys with an 8-month recovery period (ongoing)

[0282] COMPOUND A was administered SC weekly at doses of 0 (vehicle), 25, 50, and 150 mg / kg to groups of sexually mature and not sexually mature monkeys. Scheduled necropsy was conducted after 6 months of dosing (27 doses) (2-4 / sex / group) and after an 8-month recovery period (1-2 / sex / group). All doses were administered at 1 mL / kg in a vehicle / carrier consisting of 20 mM histidine, 260 mM sucrose, and 0.05% PS80, pH 6, which is consistent with the clinical formulation.

[0283] In the dosing phase, low signals of anti-COMPOUND A antibody (most below 10,000 mean signal responses) were detected in 10 of 12 animals in the control groups as57MEl\59465771.vl132301-11320observed in the control animals in the 3-month GLP study. Similarly, it was determined that the bridging method used to detect the presence of ADAs in serum can detect ADA against all parts of the COMPOUND A molecule, including the human IgGl Fc region and the complementarity determining regions. No adverse clinical signs were observed in the 10 control animals with detectable ADA. In addition, COMPOUND A exposure was not detected in the control animals; thus, the reason for the detected ADA in control animals was determined to be unlikely related to COMPOUND A exposure but rather possibly due to generic reactivity to IgG of unknown etiology.

[0284] In the thymus, decreased lymphoid cellularity was observed in the thymus of sexually mature males administered >25 mg / kg (mild to moderate), and sexually mature females and not sexually mature males and females administered >50 mg / kg (moderate to marked), correlating with decreased thymus weights (absolute and relative to body and brain weights), small thymus size noted macroscopically, and decreases in lymphocyte counts. The COMPOUND A-related decreased lymphoid cellularity observed in the thymus and associated hematology effects during the dosing phase of the study were considered non-adverse because of the low incidence and severity of the changes. There were no significant differences between the findings noted in not sexually mature and sexually mature animals. To date, no effects on reproductive organs have been observed in general toxicology studies.

[0285] Systemic exposure of COMPOUND A was mostly independent of sex or sexual maturity. At 25 mg / kg, exposure disparities were observed, likely due to ADA presence. Systemic exposure (AUCo-t and Cmax values) generally increased with increasing dose in an approximately dose-proportional manner with a mean accumulation ratio ranging approximately 2- to 5-fold from Day 1 to the end of the dosing phase. Exposure of COMPOUND A was maintained at >141,000 pg*h / mL on Day 92 throughout the dosing phase in 22 of 28 animals at >50 mg / kg despite detectable ADA.

[0286] In summary, weekly SC administration of COMPOUND A to not sexually mature and sexually mature cynomolgus monkeys for 6 months at dose levels of 25, 50, and 150 mg / kg was well tolerated. The NOAEL was considered to be 150 mg / kg / week. At the NOAEL, the mean Cmax and AUCo-t values for not sexually mature animals (sex combined) were 3260 pg / mL and 466,125 pg*h / mL, and for sexually mature animals (sex combined) were 3780 pg / mL and 540,200 pg*h / mL, respectively, after 6 months of SC weekly dosing. This corresponds to >50-fold greater than the projected steady-state Cmax (Cmax,ss) and steady-state AUC over the dosing interval (AUCtau,ss) of the proposed dose of 200 mg COMPOUND A for Phase 2 studies. The preliminary data reported here are considered 58MEl\59465771.vl132301-11320sufficient to support the dose frequency, dosing duration, and dose regimen in Phase 2 studies.Example 11 Phase 1, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, PK, and PD of COMPOUND A after SC administration in healthy subjects

[0287] The example demonstrates that COMPOUND A is safe and well tolerated in healthy human subjects (male and female subjects aged 18 to 50 years old). Further, PK studies based on the data collected in these healthy human subjects show that COMPOUND A can be administered at relatively low doses and still achieve high receptor occupancy (RO) with respect to the IL-7R receptor. Additional analysis revealed that COMPOUND A administration in healthy human subjects led to minimal ADA host response due to the low immunogenecity of COMPOUND A.

[0288] For Part 1, SAD (single ascending dose) study, the protocol defined up to 6 cohorts of 8 subjects per cohort. In each cohort, subjects were randomly assigned in a 3:1 ratio to receive either COMPOUND A or matching placebo. SAD cohort 6 was optional and was not utilized. A minimum of 7 dosed subjects evaluable for safety were required for each cohort in order to escalate to the subsequent cohort. The 5 SAD cohorts dosed in the study were 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg.

[0289] For Part 2, MAD (multiple ascending dose) study, the protocol defined up to 3 cohorts of 8 subjects per cohort. In each cohort, subjects were to be randomly assigned in a 3:1 ratio to receive either COMPOUND A or matching placebo. In the end, MAD Cohorts 2 and 3 were not enrolled per termination decision due to COVID- 19 caseload and COVID- 19 operational concerns where the study was being conducted.

[0290] Overall, the PD analyses demonstrated that COMPOUND treatment at doses that achieved >95% RO also demonstrated >90% inhibition of IL-7 signaling via phosphorylation of STAT5 (FIGs. 3A-3B). Single doses of COMPOUND A administered at 2 mg / kg or higher demonstrated sustained full RO for at least 2 weeks. Repeat administration of COMPOUND A at 1 mg / kg demonstrated durable saturation of IL-7Ra after the second dose (see FIG. 3A). In addition, the lymphocyte subsets and T cell immune function assessments demonstrated modest, dose-dependent effects on these biomarkers, consistent with the expected pharmacology when COMPOUND A fully occupies IL-7Ra. An attenuation of T-dependent antibody responses to a neo-antigen was observed at dose levels where full RO was59MEl\59465771.vl132301-11320maintained over the evaluation period while the impact of COMPOUND A treatment on delayed-type hypersensitivity (DTH) responses to a recall antigen was more variable.

[0291] The presence of ADA against COMPOUND A in human serum samples from treated subjects in phase 1 was measured using a 3-tier approach (screen, confirm, and titer) using a validated assay. After single and multiple SC administrations of COMPOUND A, generally, there was an increase in the incidence of positive ADA with time for all cohorts. While most ADA-positive samples had low titers near the sensitivity threshold of the assay, there was an increase in ADA titer with time and dose level. Based on the surrogate antibody positive control for the ADA assay, titer values <80 ng / mL reflect ADA detectable below the US FDA recommended sensitivity guideline of 100 ng / mL. Most subjects had ADA levels below this 100 ng / mL threshold, and only 8 of 34 (23.5%) subjects had titer values >80 ng / mL during the observation period.

[0292] In the context of repeat dosing with COMPOUND A in MAD Cohort 1, all 6 subjects treated with active drug developed treatment-emergent ADA responses with titers that increased to 40, 80, or 320 by Day 85, but then a decrease in ADA titer was observed upon reaching the end of the study (Day 127).

[0293] Given the ability to detect low titer antibodies in the presence of circulating drug, the assay can detect both clinically relevant and irrelevant anti-COMPOUND A antibodies. The impact of ADA on COMPOUND A exposure and PD activity was also evaluated.

[0294] Where evaluable, no impact of ADA on PK or RO was observed since the PK and RO profiles for treatment-emergent ADA-positive subjects fell within the range of observed PK profiles for ADA-negative subjects. Where the impact of ADA on PK profiles compared with ADA-negative subjects was not evaluable, concentrations generally fell within the range of expected exposures and no accelerated clearance was observed.

[0295] Across cohorts, there were no associations between the timing of positivity and any observations in the PK profiles. Many treatment-emergent ADA-positive samples occurred at or beyond Day 50 when COMPOUND A concentrations were BLQ.

[0296] Similarly, there was no apparent impact on RO, substantiating that the low titers of ADA observed in the study are unlikely to be clinically relevant. No ADA-related AEs were observed in the study. Immunogenicity and its potential clinical impact will continue to be evaluated throughout the clinical development of COMPOUND A.

[0297] In Part 1 study (SAD), while 85.7% of the subjects receiving COMPOUND 1 and 70% of the subjects receiving placebo reported treatment-emergent adverse events (TEAEs), all TEAEs were mild or moderate in intensity. 57.1% of subjects who received COMPOUND 60MEl\59465771.vl132301-11320A and 30.0% subjects who received placebo reported at least one injection site reaction (ISR) event; no ISRs were reported as severe. Transient reductions in lymphocyte counts were observed after COMPOUND A treatment centered on the Day 3 time point, corresponding to Cmax, with a more prolonged time course for the highest dose (2 mg / kg and 4 mg / kg). None of the lymphocyte count reduction events were considered clinically significant.

[0298] In Part 2 study (MAD), similarly, all TEAEs were mild or moderate in intensity and no ISR were reported as severe. Reductions in absolute lymphocyte counts were observed after COMPOUND A treatment, but none of the lymphocyte count events were considered clinically significant. A total lymphocyte count of <0.5 x 109 / L, a prespecified protocol stopping criterion, was not observed in any of the subjects during the study. There were no cases of lymphopenia as defined by the CTCAE guidance.

[0299] Overall, Phase 1 data indicates that dose up to 4 mg / kg is well tolerated in healthy human volunteers, with no observable impact on pharmacology or safety by ADA. Doses less than 3 mg / kg SC was observed to achieve full RO, and multiple administration of COMPOUND A at 1 mg / kg SC every two weeks also achieved full RO and pSTAT5 inhibition. A total lymphocyte count of <0.5 x 109 / L, a prespecified protocol stopping criterion, was not observed in any of the study subjects during the study. There were no cases of lymphopenia as defined by the Common Terminology Criteria for Adverse Events (CTCAE) guidance.Example 12: Preliminary Phase 2 Clinical Data in HumanAssessment of Antibody Serum Concentration and Receptor Occupancy (RO) by COMPOUND A in AD patients

[0300] Serum PK and blood IL-7Ra RO of COMPOUND A were evaluated in subjects dosed with 2 mg / kg (N = 5) or 3 mg / kg (N = 5) subcutaneous administration. The interim cutoff date for this analysis resulted in inclusion of data of at least 98 days (14 weeks) or 14 days (2 weeks) postdose for PK. Analyses were performed by an external unblinded pharmacometrician and results were reblinded for the Sponsor. To maintain blinding, time points or groups with N <2 were not included in the analysis. Nominal doses and nominal times of dosing and sampling were used in the analyses.

[0301] The preliminary mean serum concentration versus time profiles of free COMPOUND A after 2 and 3 mg / kg SC administration every 2 weeks are shown in FIG. 4A. After SC dosing of 2 or 3 mg / kg COMPOUND A, apparent dose-dependent exposures were61MEl\59465771.vl132301-11320observed over the first 2 weeks post-dose, with mean Day 15 trough concentrations (at predose) of 5.8 and 7.76 pg / mL, respectively. With continued dosing of 2 mg / kg every 2 weeks, 60% to 80% of patients maintained trough concentrations above 5 pg / mL, the target therapeutic concentration. Trough serum concentrations demonstrated generally high variability, with CV% ranging from approximately 40% to 90%.

[0302] Preliminary mean serum concentration versus time profiles of free COMPOUND A after 200 mg SC administration every 2 weeks are shown in FIG. 4C. After SC dosing of 200 mg COMPOUND A, minimum serum drug concentration (Cmin) at steady state >5 pg / mL was achieved in > 85% bempikibart treated-participants.Preliminary RO (mean ± standard deviation [SD]) versus time profiles after dosing of 2 and 3 mg / kg COMPOUND A SC Q2W are presented in FIG. 4B. The preliminary mean IL-7Ra RO on circulating CD3+ T cells reached complete saturation (ie, >90% RO) by Day 3 after a dose of 2 or 3 mg / kg COMPOUND A. Upon repeat subcutaneous administration of 2 mg / kg COMPOUND A Q2W, 100% of patients maintained complete RO at all time points except for one outlier at Day 43. After administration of 3 mg / kg COMPOUND A SC Q2W, 100% patients maintained complete RO above 90% up to Study Day 15. Preliminary RO (mean ± standard deviation [SD]) versus time profiles after dosing of 200 mg COMPOUND A SC Q2W are presented in FIG. 4C. Maximum systemic receptor occupancy (RO >90%) on circulating T cells was achieved in > 82% bempikibart treated-participants.

[0303] COMPOUND A has an acceptable safety profile at doses up to 3 mg / kg every 2 weeks in subjects with AD. All adverse events (AEs) were assessed as mild or moderate, and there were no reported severe AEs. Reductions in lymphocyte count below 1000 / pL, consistent with the mechanism of action, were observed in 5 subjects across both cohorts. The minimum lymphocyte count observed was 750 / pL and no adverse sequelae were reported; the subject’s lymphocyte count returned to normal upon retesting approximately 1 week later with no further reduction below normal values observed. No dose-dependent reduction in lymphocyte count was observed. The lymphocyte count reductions were generally transient and trended to within normal limits at follow-up visits. No CTCAE Grade >3 lymphopenia or associated AEs or infections were observed. No doses were delayed due to TEAEs or due to a subject’s absolute lymphocyte count (ALC) being <800 / pL (as per protocol). No other clinically significant findings in laboratory values related to COMPOUND A have been observed.62MEl\59465771.vl132301-11320

[0304] In summary, both 2 and 3 mg / kg dose groups maintained target PK threshold > 5 pg / mL (dose expected to achieve full target engagement in tissue). Maximal RO (>90%) was achieved in all subjects of both dose groups by day 3 and maintained through the entire dosing period. Safety profile is also acceptable at these two doses; particularly, no lymphopenia-associated AEs, including viral infections, have been observed.

[0305] Based on these preliminary data, a dose of 200 mg (~2.7 mg / kg) administered SC Q2W is expected to result in steady-state serum trough concentrations >5 pg / mL and maximum RO on circulating T cells in >90% of subjects throughout dosing, while expected to cause no or only minimal lymphopenia. In patients with AD, predicted median Cmax.ss and AUCtau.ss after a dose of 200 mg SC administered Q2W are > 100-fold and >50-fold lower, respectively, than exposures at the NOAEL of 150 mg / kg / week SC in cynomolgus monkeys from the 6-month GLP toxicology study (Example 7).Example 13: COMPOUND A (a Bempikibart), a Novel IL-7 / TSLP Bifunctional Receptor Antagonist Demonstrated Robust Impact on T cell maintenance and Th2 responses in T-cell driven Skin diseases

[0306] COMPOUND A (a Bempikibart), is a fully human IgGl, effector- minimized, anti-interleukin-7 receptor alpha (IL-7Ra) antagonist antibody that inhibits IL-7 and TSLP receptor signaling, and thus has potential for inhibiting THl and TH2 immune pathways.

[0307] Bempikibart was evaluated in atopic dermatitis (SIGNAL- AD) and alopecia areata (SIGNAL- AA) Phase 2a trials. Bempikibart was dosed at 200 mg Q2W by subcutaneous injections, and resulted in steady-state trough concentrations (Ctrough) >5 pg / mL in >90% of patients, with maximum receptor occupancy (RO) on circulating T cells at 0.75 pg / mL.

[0308] Since maximum receptor occupancy on T-cells in circulation is observed at 0.75 pg / mL, a concentration of 5 pg / mL was predicted to provide maximal tissue RO and clinical efficacy, assuming 15% tissue access. That is, a concentration of 5 pg / mL was predicted to lead to maximal tissue RO in skin and corresponding clinical efficacy, assuming 15% skin distribution. Mean Ctrough > 5 pg / mL and maximum RO were maintained for 6 weeks after dosing cessation. No considerable impact of immunogenicity on pharmacokinetics (PK) / RO or safety was observed.63MEl\59465771.vl132301-11320

[0309] COMPOUND A (a Bempikibart) demonstrated up to a 32.6% reduction in CD3+T cells from baseline in SIGNAL-AD, and up to 41.8% in CD3+T cells in SIGNAL-AA, indicating an effect on IL-7 signaling.

[0310] COMPOUND A / Bempikibart also demonstrated a substantial impact on Th2 biomarkers in SIGNAL- AD with a rapid decrease of eosinophils (up to 57.4%) and TARC (up to 38.5%) in AD (p<0.05 in multiple time points) and a reduction (up to 18.2% at week 18) in IgE levels. COMPOUND A / Bempikibart is a novel and potent inhibitor of IL-7Ra showing favorable PK / PD profiles and bifunctional inhibition of Th2 biomarkers and T cell counts, supporting its development in T-cell driven diseases.Example 14: Assessment ofThl and Th2 Biomarkers

[0311] COMPOUND A / Bempikibart binds IL-7Ra, the common subunit of IL-7 receptor and TSLP receptor complex, thereby blocking IL-7 and TSLP signaling. IL-7 receptor receptor is widely expressed on many T cell subsets. IL-7 regulates T cell hemostasis by enhancing the survival and proliferation of naive and memory T cells. IL-7 has also been shown to interfere with the immunosuppressive capabilities of regulatory T cells (UegS). On the other hand, TSLP has been shown to be a potent activator of antigen presenting cells such as DCs to induce TH2-mediated immune responses. For example, TSLP-stimulated DCs increase OX40L expression and production of TH2 chemokines, such as CCL17 (also known as thymus and activation regulated chemokine (TARC)) and CCL21, leading to the priming of TH2 cell development. Thus, the effects of COMPOUND A / Bempikibart to regulate THl and TH2 responses were analyzed.

[0312] A number of biomarkers for THl (CD3+T cells) and TH2 (TARC, IgE, and eosinophils) responses were analyzed in COMPOUND A / Bempikibart treated versus placebo treated group. Levels of TH2 biomarkers decreased upon treatment of COMPOUND A / Bempikibart in comparison to placebo control, with TARC levels decreased up to 39%, IgE levels deceased up to 18%, and eosinophil levels decreased up to 57% (FIG. 5A).

[0313] Treatment of COMPOUND A / Bempikibart also resulted in significant descreases in CD3+T cell levels at multiple time points post treatment, up to 40%, indicating reduction of THl responses (FIG. 5B).

[0314] These data show that COMPOUND A / Bempikibart is effective to inhibit TSLP and IL-7 mediated signaling and suppress both THl and TH2 responses.64MEl\59465771.vl132301-11320Example 15: Assessment of Adverse Events (AE)

[0315] FIG. 6 shows adverse events through week 24. 57.2% of the subjects receiving COMPOUND A / Bempikibart and 30% of the subjects receiving placebo reported treatment-emergent adverse events (TEAEs). Out of 55 participants with at least one TEAE, 50 participants are with mild (Grade 1) or moderate (Grade 2) TEAEs were mild or moderate in intensity. No drug-related Grade 3 or higher related AEs was observed. This shows favorable safety and tolerability profile of COMPOUND A / Bempikibart. This well-tolerated safety profile remained consistent throught week 36, which low incidence of infections and low incidence of lymphocyte decreases (< Grade 2).

[0316] These results demonstrate that COMPOUND A / Bempikibart was well-tolerated, with only mild / moderate drug-related AEs and two unrelated grade 3+ AEs.

[0317] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0318] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.65MEl\59465771.vl

Claims

132301-11302CLAIMS1. A method of treating a T-cell mediated inflammatory and / or an autoimmune disease in a subject (e.g., a human) in need thereof, the method comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises:(a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7- 22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT).

2. The method of claim 1, wherein the T-cell mediated inflammatory and / or an autoimmune disease is not atopic dermatitis or alopecia areata (AA).

3. The method of claim 1 or 2, wherein the composition comprising the antibody is administered to the subject to maintain serum concentration of the antibody at >5 pg / mL throughout dosing, such that the T-cell mediated inflammatory and / or an autoimmune disease is treated in the subject.

4. The method of any one of claims 1-3, wherein the antibody has a heavy chain sequence of SEQ ID NO: 23 and a light chain sequence of SEQ ID NO: 24.

5. The method of any one of claims 1-4, wherein the method rebalances Teff / mem and Tregfunction in the subject.

6. The method of any of the preceding claims, which inhibits Th2-mediated inflammation and treats an eosinophilic disease.

7. The method of any of the preceding claims, which (1) significantly reduces CD3+T cells from baseline in the subject, and / or (2) significantly reduces a Th2 biomarker in the subject, wherein the Th2 biomarker is selected from the group consisting of: eosinophil count, TARC level, and IgE level.

8. The method of any of the preceding claims, wherein said T-cell mediated inflammatory and / or an autoimmune disease is a CD3+-driven disease, a Th 1 -driven66MEl\59465771.vl132301-11320disease, a Th2-driven disease, a disease driven by both Thl and Th2, or a CD8+T cell-driven inflammation.

9. The method of claim 8, wherein said T-cell mediated inflammatory and / or an autoimmune disease is EGPA (eosinophilic granulomatosis with polyangiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), EoE (eosinophilic esophagitis), AtD, COPD (chronic obstructive pulmonary disease), asthma, alopecia, UC (ulcerative colitis), celiac disease, vitiligo, MS (multiple sclerosis), RA (rheumatoid arthritis), HS (hidradenitis suppurativa), T1D (type 1 diabetes), LN (lupus nephritis), SLE, or Autoimmune Hepatitis.

10. The method of claim 8, wherein said T-cell mediated inflammatory and / or an autoimmune disease is an eosinophilic disease selected from the group consisting of: EGPA (eosinophilic granulomatosis with poly angiitis), CRSwNP (chronic rhinosinusitis with nasal polyps), and EoE (eosinophilic esophagitis).

11. The method of any of the preceding claims, wherein the antibody is administered to the subject subcutaneously (s.c.).

12. The method of any of the preceding claims, wherein the antibody is administered once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every eight weeks (Q8W), once every twelve weeks (Q12W), or any intermittent PRN (pro re nata).

13. The method of any of the preceding claims, wherein the antibody is administered for 5-25 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) consecutive doses.

14. The method of any of the preceding claims, wherein the antibody is formulated as 100 mg / mL solution in 20 mM histidine, 260 mM sucrose, and 0.05% (w / v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.

15. The method of any one of the preceding claims, wherein the subject has impaired renal function (e.g., mildly impaired renal function (such as a glomerular filtration rate <60 mL / min and / or the presence of albuminuria >30 mg / d), moderately impaired renal function (such as a glomerular filtration rate <45 mL / min), or severely impaired renal function (such as a glomerular filtration rate <30 mL / min).67MEl\59465771.vl132301-1132016. The method of any one of the preceding claims, wherein the subject is further being treated by or has been treated by a second therapeutic agent effective to treat the T- cell mediated inflammatory and / or an autoimmune disease.68MEl\59465771.vl

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