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US-20260125435-A1 - IL-10 VARIANT MOLECULES AND METHODS FOR TREATING INFLAMMATORY DISEASE AND ONCOLOGY

US20260125435A1US 20260125435 A1US20260125435 A1US 20260125435A1US-20260125435-A1

Abstract

The application relates to compositions or formulations comprising variant IL-10 molecules, fusion proteins, and chimeric proteins thereof useful for the treatment of cancer, inflammatory diseases or disorders, and autoimmune diseases or disorders.

Inventors

  • John Mumm

Assignees

  • Deka Biosciences, Inc.

Dates

Publication Date
20260507
Application Date
20251114

Claims (10)

  1. 1 . A fusion protein comprising an interleukin 10 (IL10) and a single chain variable fragment (scFv), the fusion protein represented by formula (I) (IL10)-L-X 1 -L-X 2 -L-(IL10) (Formula I) wherein “IL10” is a monomer of IL10 comprising s sequence selected from SEQ ID NO: 15 or 57; “X 1 ” is a variable heavy (VH) domain of a first antibody, the VH comprising three complementarity determining regions (CDRs) and “X 2 ” is a variable light (VL) domain of the first antibody, the VL comprising three CDRs, wherein X 1 and X 2 together form the scFv; and “L” is a linker.
  2. 2 . The fusion protein according to claim 1 , wherein the three CDRs of X 1 and the three CDRs of X 2 are engrafted with CDRs from a VH region and a VL region from a second antibody.
  3. 3 . The fusion protein according to claim 1 , wherein the first antibody is specific for Ebola.
  4. 4 . The fusion protein according to claim 3 , wherein the first antibody specific for Ebola is engrafted with CDRs from a second antibody.
  5. 5 . The fusion protein according to claim 4 , wherein the second antibody is specific for epidermal growth factor receptor (EGFR), CD52, PD-L1, PD-1, TIM3, BTLA, LAG3, CTLA4, CD20, CD47, GD-2, HER2, EpCAM, ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, VCAM, FAPα, 5T4, Trop2, EDB-FN, TGFβ Trap, MadCam, β7 integrin subunit, α4β7 integrin, α4 integrin, SR-A1, SR-A3, SR-A4, SR-A5, SR-A6, SR-B, dSR-C1, SR-D1, SR-E1, SR-F1, SR-F2, SR-G, SR-H1, SR-H2, SR-11, SR-J1, HIV, or Ebola.
  6. 6 . The fusion protein according to claim 2 , wherein the second antibody is specific for epidermal growth factor receptor (EGFR), CD52, PD-L1, PD-1, TIM3, BTLA, LAG3, CTLA4, CD20, CD47, GD-2, HER2, EpCAM, ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, VCAM, FAPα, 5T4, Trop2, EDB-FN, TGFβ Trap, MadCam, β7 integrin subunit, α4β7 integrin, α4 integrin, SR-A1, SR-A3, SR-A4, SR-A5, SR-A6, SR-B, dSR-C1, SR-D1, SR-E1, SR-F1, SR-F2, SR-G, SR-H1, SR-H2, SR-I1, SR-J1, HIV, or Ebola.
  7. 7 . The fusion protein according to claim 1 , wherein X 1 and X 2 comprise modifications that reduce the antigenicity in a subject.
  8. 8 . The fusion protein according to claim 1 , wherein Lis SEQ ID No: 31 or 54.
  9. 9 . A pharmaceutical composition comprising a therapeutically effect amount of the fusion protein according to claim 1 .
  10. 10 . The pharmaceutical composition according to claim 9 , wherein the pharmaceutical composition further comprises pharmaceutically acceptable carrier, excipient, preservatives, stabilizers, or any combination thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of Ser. No. 18/657,437, entitled “IL-10 VARIANT MOLECULES AND METHODS FOR TREATING INFLAMMATORY DISEASE AND ONCOLOGY”, filed on May 7, 2024, which is a continuation of U.S. patent application Ser. No. 17/322,394, entitled “IL-10 VARIANT MOLECULES AND METHODS FOR TREATING INFLAMMATORY DISEASE AND ONCOLOGY”, filed on May 17, 2021, which is continuation of U.S. patent application Ser. No. 17/002,537, entitled “IL-10 VARIANT MOLECULES AND METHODS FOR TREATING INFLAMMATORY DISEASE AND ONCOLOGY” and filed on Aug. 25, 2020, which is a divisional of U.S. patent application Ser. No. 16/811,718, entitled “IL-10 VARIANT MOLECULES AND METHODS OF TREATING INFLAMMATORY DISEASE AND ONCOLOGY” and filed on Mar. 6, 2020, and issued U.S. Pat. No. 10,858,412, dated Dec. 8, 2020, which claims priority to U.S. Provisional Patent Application No. 62/814,669, filed Mar. 6, 2019, U.S. Provisional Patent Application No. 62/899,504, filed Sep. 12, 2019, and U.S. Provisional Patent Application No. 62/962,332, filed Jan. 17, 2020, the disclosures of each is herein incorporated by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (039451-00186_Sequence-Listing.xml; Size: 142,166 bytes; and Date of Creation: May 7, 2024) is herein incorporated by reference in its entirety. INTRODUCTION The application relates to variant forms of Interleukin 10 (IL-10) that include modifications to the IL-10 receptor binding region and/or the domains responsible for the inter-domain angles that exists in the IL-10 molecule. By modifying one or both of these domains in IL-10, the inventors have surprisingly found that the resulting biological function of the IL-10 receptor may be tuned or modulated to elicit a specific biological response. The application also relates to a half-life extended IL-10 or IL-10 variant molecule that include non-protein based serum extension moieties as well as protein based extension modalities. The Application also relates to fusion proteins comprising the IL-10 variant molecules. BACKGROUND IL-10 has been described as cytokine synthesis inhibitory factor, due to its capacity to inhibit both (i) pro-inflammatory cytokine secretion by monocytes/macrophages in response to lipopolysaccharide, and (ii) interleukin 2 (IL-2) secretion and proliferation of CD4+ T cells. When viral analogues of IL-10 were discovered and reported to share similar or identical functions to human IL-10, it was presumed that these viral analogs of IL-10 enhanced viral virulence by adopting the function of a suppressive cytokine found in the human genome. Further investigation of the suppressive effects of IL-10 was made possible by the generation of the IL-10 knockout mice that develop chronic enterocolitis. The data generated from these mice clearly illustrated that IL-10 knockout mice develop severe inflammation throughout the gastrointestinal track, predominantly through chronic inflammatory cytokine secretion by monocytes/macrophages and CD4+ T cells, which is consistent with initial in vitro observations. Collectively the data implied that IL-10 exerted a dominant role in suppressing inflammation. In particular, patients lacking functional IL-10 receptors, or the ability to produce IL-10 exhibited an increased predisposition to developing inflammation associated diseases of the gastrointestinal track. Multiple clinical trials were conducted to evaluate the anti-inflammatory function of IL-10 in context of psoriasis, rheumatoid arthritis, and Crohn's disease. In general, recombinant human IL-10 (rHuIL-10) treatment was found to be safe but lacking in efficacy. In particular, treating Crohn's patients with rHuIL-10 lead to an inverse dose response, where low doses appeared to moderately inhibit inflammation and the suppressive effect was lost at high doses. Rigorous analysis of the final Crohn's study revealed that patients dosed with 10 and 20 μg/kg rHuIL-10 exhibited increased serum concentrations of interferon gamma (IFNγ) and Neopterin. IFNγ is known to worsen the pathogenesis of inflammatory bowel disease, and Crohn's disease. The data suggests that at high doses, treatment with IL-10 induces IFNγ, which, in turn, will exacerbate inflammatory disease. Further analysis of IL-10 effects in healthy humans suggests that administration of IL-10 before exposure to the pro-inflammatory factor lipopolysaccharide (LPS) inhibits production of pro-inflammatory cytokines. However, administering rHuIL-10 after exposure to LPS enhanced the secretion of pro-inflammatory cytokines. Since LPS is a product of both normal and foreign gut bacteria in patients with Inflammatory Bowel Disease (IBD), these patients will never be “free” of LPS and therefore will never be in a state where IL-10 treatment could be applied prior to LPS. Thus, these data suggests that Crohn's and patients with other inflammatory diseases will never