Methods for treating systemic lupus erythematosus with an anti-apolipoprotein B antibody
Inventors
Nilsson, Jan • Abbott, Ryan Benjamin • Liang, Bertrand C. • Farina, Christopher John • Ruiz, Stacey
Assignees
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Publication Number
US-10858422-B2
Publication Date
2020-12-08
Expiration Date
Abstract
Described herein are peptides and antibodies for prevention and/or therapeutic treatment of mammals, including humans, against systemic lupus erythematosus, as well as diagnosing the presence or absence of antibodies related to increased or decreased risk of developing SLE and/or to disease grading, staging, and/or prognosis.
Core Innovation
The disclosure relates to compositions and methods for treating systemic lupus erythematosus (SLE) and SLE-associated cardiovascular disease, including accelerated atherosclerosis, using an antibody that binds oxidized fragments of apolipoprotein B100 (ApoB100). The antibody targets an oxidized ApoB100 epitope corresponding to peptide P45 (SEQ ID NO:45) and is administered as a therapeutically or prophylactically effective passive immunization.
The disclosed antigenic basis includes ApoB100-derived peptide libraries (P1–P302; SEQ ID NOs:1–302) and peptide exemplars such as P210 and P45. CD8+ T-cell activation is described using ApoB100 peptides, and passive immunization is supported by an anti-oxidized-ApoB antibody (orticumab/2D03) with defined complementarity determining regions and sequence-defined variable regions.
The report describes altered ApoB100 peptide autoantibody isotypes in SLE subjects, including reduced P45 IgM and P210 IgG, with context-specific changes for oxidized and malondialdehyde-modified ApoB peptides. These findings are associated with prevalent cardiovascular disease, increased carotid intima-media thickness, and greater organ damage, and provide rationale for oxidized/MDA-modified ApoB peptide targeting in SLE.
Claims Coverage
The consolidated claim coverage includes three independent claims. Across these claims, the inventive features include passive immunization for SLE using antibodies that bind oxidized ApoB100 fragments, antibody/antibody fragment treatment defined by specific HCDR and LCDR sequences, and treatment of SLE-associated atherosclerosis using an ApoB100 fragment-binding antibody with sequence-defined variable regions.
Passive immunization for treating SLE with a sequence-defined oxidized ApoB100-binding antibody
A method for treating systemic lupus erythematosus (SLE) in a subject in need thereof by passive immunization, comprising administering a therapeutically or prophylactically effective amount of an antibody that binds at least one oxidized fragment of apolipoprotein B100 (ApoB100), wherein the antibody comprises a variable heavy region (V_H) and a variable light region (V_L) with V_H comprising the sequence set forth in SEQ ID NO:324 and V_L comprising the sequence set forth in SEQ ID NO:325.
Treating SLE with an antibody defined by specific HCDR and LCDR sequences
A method for treating, reducing the severity of, slowing progression of or inhibiting systemic lupus erythematosus (SLE) in a subject, comprising administering an effective amount of an antibody or antibody fragment comprising HCDR1, HCDR2 and HCDR3 whose sequences comprise SEQ ID NOs:318, 319 and 320, respectively, and LCDR1, LCDR2 and LCDR3 whose sequences comprise SEQ ID NOs:321, 322 and 323, respectively.
Atherosclerosis treatment in SLE using an ApoB100 fragment-binding antibody with defined HCDR/LCDR
A method for treating, reducing the severity of, slowing progression of or inhibiting atherosclerosis in a subject exhibiting symptoms of or having been diagnosed with systemic lupus erythematosus (SLE), comprising administering an effective amount of an antibody or antibody fragment capable of binding to a fragment of apolipoprotein B100 (ApoB100), wherein the fragment comprises an amino acid sequence of SEQ ID NO:45 or an active site thereof, and wherein the antibody or antibody fragment comprises HCDR1, HCDR2 and HCDR3 whose sequences comprise SEQ ID NOs:318, 319 and 320, respectively, and one, two or three LCDRs whose sequences comprise SEQ ID NOs:321, 322 and 323, respectively.
Across the independent claims, the core coverage is directed to passive immunization for SLE and SLE-associated atherosclerosis using antibodies or antibody fragments that bind oxidized ApoB100 fragments, with the antibody identity further defined by sequence-defined V_H/V_L regions or by specific HCDR and LCDR sequences.
Stated Advantages
Reduce the severity of, slow progression of, or inhibit systemic lupus erythematosus (SLE).
Treat, reduce the severity of, slow progression of, or inhibit atherosclerosis in a subject with systemic lupus erythematosus (SLE).
Provides diagnostic/prognostic assessment by quantifying ApoB100 autoantibodies and soluble Fas, TNF-R1 and TRAIL-R2, and assesses treatment efficacy by the direction of ApoB100 autoantibody level change.
Documented Applications
Treating systemic lupus erythematosus (SLE) in a subject by passive immunization with an antibody that binds oxidized ApoB100 fragments.
Treating, reducing the severity of, slowing progression of, or inhibiting SLE by administering an antibody or antibody fragment with HCDR and LCDR sequences comprising SEQ ID NOs:318–323.
Treating, reducing the severity of, slowing progression of, or inhibiting atherosclerosis in a subject exhibiting symptoms of or having been diagnosed with SLE, using an ApoB100 fragment-binding antibody or antibody fragment that includes SEQ ID NO:45 binding and HCDR/LCDR sequence constraints.
Diagnostic/prognostic assays that quantify ApoB100 autoantibodies and soluble apoptosis-signaling receptors (Fas, TNF-R1, TRAIL-R2), with treatment efficacy assessed by the direction of ApoB100 autoantibody level change.
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