Fusion protein constructs comprising anti-C3d antibody and CR1 polypeptide
Inventors
CURTIS, MICHAEL STEVEN • Storek, Michael • VIOLETTE, SHELIA MARIE • Kalled, Susan L. • FAHNOE, KELLY C. • HUANG, CHENG RAN • STARK, ELLEN GARBER • TAYLOR, FREDERICK ROBBINS • Caravella, Justin Andrew • Holers, Vernon Michael
Assignees
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Publication Number
US-11053305-B2
Publication Date
2021-07-06
Expiration Date
Abstract
Provided herein are fusion protein constructs that can bind a complement-associated antigen, comprising a targeting moiety and a complement modulator protein, or a fragment thereof or a variant thereof. The targeting moiety is an antibody or an antigen binding fragment thereof, in some examples. Further provided are methods of using the fusion protein constructs, for example, in treating complement mediation conditions.
Core Innovation
The invention relates to a fusion protein construct in which an antibody or an antigen binding fragment specifically binds complement protein 3d (C3d). The antibody or antigen binding fragment comprises heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) and light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3), with the CDR regions defined by specific amino acid sequences including SEQ ID NO: 29, SEQ ID NO: 260, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34.
The antibody portion is fused to a complement modulator polypeptide comprising CR1 or a biologically active fragment thereof. The document further describes linker features connecting the antibody or antigen binding fragment to the complement modulator polypeptide, attachment locations in some embodiments, and alternative complement modulator polypeptide amino acid sequences.
The disclosure also characterizes the constructs through binding and functional rationale involving reduced binding metrics to deposited C3 fragments, reduced complement activity versus a comparator, complement inhibition, and C3 deposition. It further includes extensive definitions of complement system components, targeting moieties, Fc region and Fcγ receptor-related terms, and epitope mapping approaches, including PEPperMAP linear epitope mapping.
Claims Coverage
The independent claims cover two main inventive aspects: a C3d-binding antibody or antigen-binding fragment fused to a CR1 complement modulator polypeptide with explicitly defined CDR amino acid sequences, and a standalone antibody or antigen-binding fragment defined by the same CDR sequence sets. Across the claims, the core inventive features are the specified CDR sequences for C3d binding and the fusion of that antibody to a CR1-based complement modulator polypeptide.
C3d-binding antibody fused to CR1 complement modulator
A fusion protein construct comprising an antibody or an antigen binding fragment that specifically binds complement protein 3d (C3d), wherein the antibody or antigen binding fragment comprises heavy chain CDR-H1 comprising SEQ ID NO: 29, CDR-H2 comprising SEQ ID NO: 260, and CDR-H3 comprising SEQ ID NO: 31, and light chain CDR-L1 comprising SEQ ID NO: 32, CDR-L2 comprising SEQ ID NO: 33, and CDR-L3 comprising SEQ ID NO: 34; and a complement modulator polypeptide comprising CR1 or a biologically active fragment thereof.
C3d-binding antibody defined by CDR sequence sets
An antibody or an antigen-binding fragment comprising a heavy chain with CDR-H1, CDR-H2, and CDR-H3 comprising SEQ ID NOS: 29, 260 and 31, and a light chain with CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS: 32, 33 and 34.
Across the independent claims, the claim coverage centers on C3d-specific binding via explicitly defined heavy- and light-chain CDR amino acid sequence sets, combined either with a fusion to a CR1 complement modulator polypeptide or as an antibody/antigen-binding fragment by itself.
Stated Advantages
Reduced binding metrics to deposited C3 fragments.
Reduced complement activity versus a comparator.
Complement inhibition and C3 deposition are described as functional rationale.
Documented Applications
Therapeutic indications for complement-mediated diseases are documented.
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