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US-12616749-B2 - Methods for treatment of psoriasis with an anti-oxLDL antibody

US12616749B2US 12616749 B2US12616749 B2US 12616749B2US-12616749-B2

Abstract

Compositions and methods for treating a subject with psoriasis are provided, including an inhibitor of oxidized low density lipoprotein (LDL), malondialdehyde-modified epitope in LDL or native LDL for administration. Exemplary inhibitors of oxidized or malondialdehyde-modified LDL include orticumab, a variant antibody or peptides capable of binding oxidized or malondialdehyde-modified LDL, which results in improvement in conditions of psoriasis even in patients that are refractory to ultraviolet A/B therapy and topical steroids.

Inventors

  • Bertrand C. Liang
  • Stacey Ruiz
  • Christopher John Farina

Assignees

  • ABCENTRA, LLC

Dates

Publication Date
20260505
Application Date
20240621

Claims (18)

  1. 1 . A method for treating, reducing the severity of, slowing progression of, or inhibiting psoriasis or psoriatic arthritis in a subject in need thereof, comprising: administering to the subject an effective amount of an antibody or antibody fragment comprising a heavy chain determining region (HCDR) 1 having the sequence of SEQ ID NO: 2, an HCDR 2 having the sequence of SEQ ID NO: 3, and an HCDR 3 having the sequence of SEQ ID NO: 4, a light chain determining region (LCDR) 1 having a sequence of SEQ ID NO: 5, an LCDR 2 having a sequence of SEQ ID NO: 6, and an LCDR 3 having a sequence of SEQ ID NO: 7.
  2. 2 . The method of claim 1 , wherein the antibody comprises the variable heavy region (VH) of SEQ ID NO: 8, the variable light region (VL) of SEQ ID NO: 9, or both.
  3. 3 . The method of claim 2 , wherein the antibody comprises the heavy chain of SEQ ID NO: 10, the light chain of SEQ ID NO: 11, or both.
  4. 4 . The method of claim 1 , wherein the psoriasis is plaque psoriasis.
  5. 5 . The method of claim 4 , wherein the subject does not have a non-plaque form of psoriasis, wherein the non-plaque form comprises erythrodermic, guttate or pustular psoriasis.
  6. 6 . The method of claim 1 , wherein the subject is a human, the antibody is orticumab, and orticumab is administered subcutaneously at a dose of about 330 mg/month for about 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.
  7. 7 . The method of claim 1 , wherein the antibody or antibody fragment is administered at 1-10 μg/kg.
  8. 8 . The method of claim 1 , wherein the antibody or antibody fragment is administered at 10-100 μg/kg.
  9. 9 . The method of claim 1 , wherein the antibody or antibody fragment is administered at 100-500 μg/kg.
  10. 10 . The method of claim 1 , wherein the subject further exhibits symptoms of atherosclerosis before the administration, and after the administration the subject has reduced plaque volume.
  11. 11 . The method of claim 1 , further comprising administering a topical corticosteroid, a vitamin D analogue, a topical retinoid, a keratolytic agent, coal tar, ultraviolet A, ultraviolet B, an anti-tumor necrotic factor (TNF) antibody, an anti-interleukin (IL)-12/23 antibody, an anti-IL-23 antibody, an anti-IL-17 antibody, or a combination thereof, wherein the vitamin D analogue comprises calcitriol, calcipotriene, maxacalcitol or tacalcitol.
  12. 12 . The method of claim 1 , wherein the subject exhibits symptoms of psoriasis or psoriatic arthritis and is refractory to UVA therapy, UVB therapy, a topical steroid, or a combination thereof.
  13. 13 . The method of claim 1 , wherein the subject has an elevated amount of tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), C-reactive protein (CRP), or a combination thereof, compared to a control subject free of psoriasis or psoriatic arthritis.
  14. 14 . The method of claim 1 , further comprising selecting a subject exhibiting symptoms of psoriasis or psoriatic arthritis or a subject who has been diagnosed with psoriasis or psoriatic arthritis.
  15. 15 . A method for passive immunization of a subject, wherein a therapeutically effective amount of an antibody or antibody fragment is administered for treatment of psoriasis or psoriatic arthritis, wherein the antibody comprises an HCDR 1 having the sequence of SEQ ID NO: 2, an HCDR 2 having the sequence of SEQ ID NO: 3, and an HCDR 3 having the sequence of SEQ ID NO: 4, an LCDR 1 having a sequence of SEQ ID NO: 5, an LCDR 2 having a sequence of SEQ ID NO: 6, and an LCDR 3 having a sequence of SEQ ID NO: 7.
  16. 16 . The method of claim 15 , wherein the antibody comprises the variable heavy region (VH) of SEQ ID NO: 8, the variable light region (VL) of SEQ ID NO: 9, or both.
  17. 17 . The method of claim 15 , wherein the antibody comprises the heavy chain of SEQ ID NO: 10, the light chain of SEQ ID NO: 11, or both.
  18. 18 . The method of claim 15 , wherein the subject is diagnosed with psoriasis or psoriatic arthritis and characterized by an elevated amount of tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), C-reactive protein (CRP), or a combination thereof, compared to a subject free of psoriasis or psoriatic arthritis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation of application Ser. No. 17/058,537 filed on Nov. 24, 2020, which claims benefit to International Patent Application No. PCT/US2019/034423 filed on May 29, 2019, which claims benefit to U.S. Provisional Application 62/677,590 filed on May 29, 2018. The entire contents of these applications are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 11, 2024, is named 51473-003003_Sequence_Listing_6_11_24 and is 13,194 bytes in size. FIELD OF INVENTION This invention relates to the treatment of psoriasis in a patient and the treatment of atherosclerosis in patients with psoriasis. BACKGROUND All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. Psoriasis is a chronic inflammatory disease that manifests as scaly patches of skin, which occurs due to hyperproliferation of keratinocytes and activated immune cells. Treatment typically involves immune mediation, such as the use of anti-inflammatory agents including topical corticosteroids, ultraviolet (UV) A and B light therapy, or cytotoxic agents. In patients who are refractory to topical treatment and/or UVA/B therapy, anti-inflammatory biologic therapies are initiated, such as monoclonal antibodies against TNFα, IL-12/23, and IL-17 or antibodies against IL-23 only. Many systemic treatments for psoriasis have adverse cardiovascular effects, such as dyslipidemia and hypertension. The highly oxidative environment produced by psoriatic inflammation promotes oxidation of LDL and endothelial dysfunction, two key contributors to atherosclerosis development. Oxidized LDL (oxLDL) forms when LDL infiltrates the subendothelial space in the arterial wall and comes into contact with reactive oxygen species, which are highly upregulated in psoriasis. Through the process of LDL oxidation, various adducts (e.g., malondialdehyde [MDA]) are formed, which further modify LDL (i.e., MDA-LDL). The oxidized/modified LDL acts in a myriad of ways supporting inflammation and atherosclerosis. Without being bound by any theory, such molecules affect the proliferation and migration of vascular smooth muscle cells (VSMCs) likely through binding to lectin-type oxidized LDL receptor 1 (LOX-1), which are pivotal events in atherosclerotic plaque progression. The oxidized/modified LDL is also taken up by macrophages, which become foam cells and stimulate a pro-inflammatory response that results in both the build-up of a necrotic core in the vessel plaque and recruitment of additional monocytes to the plaque. This process provides a feed-forward loop of chronic inflammation that contributes to plaque growth, as well as plaque instability. Elevated levels of oxLDL and MDA-LDL, as well as LOX-1, have been found both in the plaque and plasma of patients at risk for developing CVD and inflammation. Therefore, it is an objective of the present invention to provide compositions for use in and methods for treating, reducing the severity or likelihood of psoriasis in a subject. SUMMARY OF THE INVENTION The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope. Methods for treating, reducing the severity of, slowing progression of or inhibiting psoriasis in a subject in need thereof are provided, which include administering to the subject an effective amount of an antibody or antibody fragment capable of binding to a fragment of apolipoprotein B100 (ApoB100), wherein the fragment of ApoB100 comprises an amino acid sequence of SEQ ID No.: 1 or an active site thereof, and wherein the antibody comprises one, two or three heavy chain complementarity determining regions (HCDRs) selected from the group consisting of HCDR 1 (HCDR1), HCDR 2 (HCDR2) and HCDR 3 (HCDR3) sequences of SEQ ID Nos: 2, 3 and 4, respectively, and one, two or three light chain complementarity determining regions (LCDRs) selected from the group consisting of LCDR 1 (LCDR1), LCDR 2 (LCDR2) and LCDR 3 (LCDR3) sequences of SEQ ID Nos: 5, 6 and 7, respectively. Further embodiments provide that the method of treating, reducing the severity or likelihood of psoriasis includes administering one or more therapeutic agents or therapies in combination (e.g., sequentially or concurrently)