US-20260125462-A1 - COMPOUNDS AND METHODS TARGETING INTERLEUKIN-19

US20260125462A1US 20260125462 A1US20260125462 A1US 20260125462A1US-20260125462-A1

Abstract

The present invention provides compounds and methods targeting human interleukin-19, including therapeutic antibodies, pharmaceutical compositions and diagnostic applications useful in the field of immune-mediated diseases including psoriasis, atopic dermatitis, psoriatic arthritis, bronchial asthma and diabetic nephropathy.

Inventors

Richard Earl Higgs, Jr.
Robert John Konrad
Brian Jeffrey Nickoloff
Robert William Siegel, II

Assignees

ELI LILLY AND COMPANY

Dates

Publication Date: 20260507
Application Date: 20250909

Claims (8)

1 . An antibody which binds to human IL-19, said antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3 selected from: a. a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 having at least 95% amino acid sequence homology to the amino acid sequence of a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 1; b. grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 having at least 95% amino acid sequence homology to the amino acid sequence of a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 2; or c. grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 having at least 95% amino acid sequence homology to the amino acid sequence of a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 3.
2 . The antibody of claim 1 , wherein LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3 are selected from: a. a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 1 and having the amino acid sequence of the grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 1; b. a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 2 and having the amino acid sequence of the grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 2; or c. a grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 3 and having the amino acid sequence of the grouping of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 provided in Table 3.
3 . The antibody of claim 1 , wherein the LCVR and the HCVR are selected from: a. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 66 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 70; b. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 74 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 78; c. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 82 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 86; d. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 34 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 38; c. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 42 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 46; f. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 50 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 54; g. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 58 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 62; h. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 294 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 298; and i. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 302 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 306.
4 . The antibody of claim 2 , wherein LCVR and HCVR are selected from: a. the LCVR having the amino acid sequence of SEQ ID NO: 66 and the HCVR having the amino acid sequence of SEQ ID NO: 70; b. the LCVR having the amino acid sequence of SEQ ID NO: 74 and the HCVR having the amino acid sequence of SEQ ID NO: 78; c. the LCVR having the amino acid sequence of SEQ ID NO: 82 and the HCVR having the amino acid sequence of SEQ ID NO: 86; d. the LCVR having the amino acid sequence of SEQ ID NO: 34 and the HCVR having the amino acid sequence of SEQ ID NO: 38; e. the LCVR having the amino acid sequence of SEQ ID NO: 42 and the HCVR having the amino acid sequence of SEQ ID NO: 46; f. the LCVR having the amino acid sequence of SEQ ID NO: 50 and the HCVR having the amino acid sequence of SEQ ID NO: 54; g. the LCVR having the amino acid sequence of SEQ ID NO: 58 and the HCVR having the amino acid sequence of SEQ ID NO: 62; h. the LCVR having the amino acid sequence of SEQ ID NO: 294 and the HCVR having the amino acid sequence of SEQ ID NO: 298; and i. the LCVR having the amino acid sequence of SEQ ID NO: 302 and the HCVR having the amino acid sequence of SEQ ID NO: 306.
5 . The antibody of claim 1 further comprising a IgG1 heavy chain.
6 . The antibody of claim 1 further comprising a kappa light chain.
7 . A method of treating an immune-mediated disease comprising administering to a patient in need thereof an effective amount of an antibody of claim 1 .
8 . The method of claim 7 , wherein the immune-mediated disease is one of: PsO, AD, PsA and renal nephropathy.

Description

The present application is filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “X20963A.xml” created Jan. 6, 2023 and is 397,757 bytes in size. The Sequence Listing information in ST.26 XML format is incorporated by reference in its entirety. The present invention is in the field of medicine. More particularly, the present invention relates to compounds, pharmaceutical compositions, and methods which include an antibody directed against human interleukin-19 (IL-19). The compounds and methods of the present invention are expected to be useful in the field of autoimmune and chronic inflammatory diseases (collectively referred to herein as, immune-mediated diseases), particularly diseases such as psoriasis (Ps0), atopic dermatitis (AD), diabetic nephropathy (DN), bronchial asthma (BA), psoriatic arthritis (PsA) and the like, including treatment thereof and diagnostic applications relating thereto. Interleukin-19 (IL-19) is a cytokine reported to belong to the interleukin-10 cytokine family (which includes IL-10, 20, 22 and 26 as well as some virus-encoded cytokines). IL-19 has been reported to have involvement in the IL-20R complex signaling pathway and to be expressed in resting monocytes, macrophages, B cells, and epithelial cells including keratinocytes. Autoimmune diseases arise from the body's production of an immune response against its own tissue. Autoimmune diseases are often chronic and can be debilitating and even life-threatening. Ps0 is a chronic autoimmune disease with systemic manifestations including psoriatic arthritis, cardiovascular disease, metabolic syndrome and affective disorders. AD, along with many other forms of chronic autoimmune diseases such as Ps0, RA, AxSpA and PsA, affect the axial and/or peripheral skeleton. Current FDA approved treatments for immune-mediated diseases include corticosteroids, often used to treat acute inflammation, and bioproducts targeting TNFα or interleukin-12 and 23. Although these treatments have demonstrated efficacy in reducing symptoms for a subset of patients, a large percentage of patients remain nonresponsive or experience a loss of response to the currently available treatments. For autoimmune diseases such as Ps0, ixekizumab is an FDA approved therapeutic antibody targeting IL-17A in which 90% of patients achieved a 75% reduction in the Psoriasis Assessment Skin Involvement (PASI) score (e.g. PASI 75). However, PASI assessments rely on subject inputs that can be difficult to assess in certain circumstances. To date, an objective, sensitive, and reproducible blood-based biomarker for assessing and informing clinical management of Ps0, and other immune-mediated diseases such as AD, DN and BA does not exist. Thus, there remains an unmet need for compounds, pharmaceutical compositions, and methods useful as therapeutics for, and/or in diagnostic applications relating to, immune-mediated diseases such as Ps0, AD, BA, DN and the like. Accordingly, in certain embodiments, the present invention provides antibodies directed against human IL-19. According to some embodiments, the present invention provides antibodies which comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3 selected from the groupings of CDR combinations provided in Table 1, 2 or 3. In some embodiments, the LCVR comprises CDRs LCDR1, LCDR2 and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3 having amino acid sequences with at least 95% homology to the amino acid sequences selected from the groupings of CDR combinations provided in Table 1, 2 or 3. According to particular embodiments, the present invention also provides antibodies comprising a LCVR and a HCVR selected from: a. the LCVR having the amino acid sequence of SEQ ID NO: 66 and the HCVR having the amino acid sequence of SEQ ID NO: 70;b. the LCVR having the amino acid sequence of SEQ ID NO: 74 and the HCVR having the amino acid sequence of SEQ ID NO: 78;c. the LCVR having the amino acid sequence of SEQ ID NO: 82 and the HCVR having the amino acid sequence of SEQ ID NO: 86;d. the LCVR having the amino acid sequence of SEQ ID NO: 34 and the HCVR having the amino acid sequence of SEQ ID NO: 38;e. the LCVR having the amino acid sequence of SEQ ID NO: 42 and the HCVR having the amino acid sequence of SEQ ID NO: 46;f. the LCVR having the amino acid sequence of SEQ ID NO: 50 and the HCVR having the amino acid sequence of SEQ ID NO: 54; andg. the LCVR having the amino acid sequence of SEQ ID NO: 58 and the HCVR having the amino acid sequence of SEQ ID NO: 62. According to even more particular embodiments, the present invention also provides antibodies comprising a LC and a HC selected from, or having amino acid sequences with at least 95% homology to the amino acid sequences of: a. the LC having the amin