Fusion protein constructs comprising anti-C3d antibody and factor H
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-11053306-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 provides a fusion protein construct that combines an antibody or an antigen binding fragment thereof that specifically binds complement protein 3d (C3d) with a complement modulator polypeptide. The antibody component comprises a heavy chain with CDR-H1, CDR-H2, and CDR-H3 and a light chain with CDR-L1, CDR-L2, and CDR-L3, defined by specified amino acid sequences.
The complement modulator polypeptide comprises factor H or a biologically active fragment thereof. The disclosure further describes linkage of the antibody or antigen-binding fragment to the complement modulator polypeptide by linkers, and includes antibody variable-region terminology and framework region numbering conventions for defining the CDR boundary options and VH/VL framework regions.
The fusion constructs are described as combining the C3d-binding antibody component with factor H-derived complement modulation. The disclosure also addresses fusion orientation and multivalency, including mono-, tri-, and tetravalent configurations, and compares targeted versus non-targeted approaches.
Claims Coverage
The claim coverage centers on a fusion protein architecture with two core inventive features: a C3d-binding antibody or antigen-binding fragment defined by specific heavy- and light-chain CDR sequences, and a complement modulator polypeptide comprising factor H or a biologically active fragment.
C3d-binding antibody with defined heavy- and light-chain CDR sequences
A fusion protein construct comprising an antibody or an antigen binding fragment thereof that specifically binds to complement protein 3d (C3d), wherein the heavy chain comprises CDR-H1, CDR-H2, and CDR-H3 defined by SEQ ID NO: 29, SEQ ID NO: 260, and SEQ ID NO: 31, and the light chain comprises CDR-L1, CDR-L2, and CDR-L3 defined by SEQ ID NO: 32, SEQ ID NO: 33, and SEQ ID NO: 34.
Factor H complement modulator polypeptide
The fusion protein construct further comprises a complement modulator polypeptide, wherein the complement modulator polypeptide comprises factor H or a biologically active fragment thereof.
Fusion construct architecture combining antibody fragment and complement modulator
A fusion protein construct comprising the C3d-specific antibody or antigen binding fragment and the complement modulator polypeptide comprising factor H or a biologically active fragment thereof.
Linker connecting antibody-binding part to complement modulator
A linker connecting the antibody or antigen binding fragment to a complement modulator polypeptide.
Linker attached at the heavy-chain C-terminus with a specified linker sequence
A linker attached to the C-terminus of the heavy chain and includes the amino acid sequence of SEQ ID NO: 138.
Enumerated heavy-chain/light-chain sequence-architecture combinations
A fusion protein construct selected from specified combinations of heavy chain-containing polypeptides and light chain-containing polypeptides, wherein the polypeptides comprise particular N- to C-terminal amino acid sequences given by SEQ ID NO combinations including SEQ ID NO: 72, SEQ ID NO: 108, SEQ ID NO: 138, SEQ ID NO: 282, SEQ ID NO: 279, SEQ ID NO: 285, and SEQ ID NO: 284.
Overall, the claim coverage focuses on fusion constructs that pair a C3d-specific antibody component defined by explicit CDR amino acid sequence assignments with a complement modulator polypeptide containing factor H or a biologically active fragment, with further dependent features including linkers and sequence variants.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment indications for complement-associated diseases including aHUS, PNH, lupus nephritis, RA, and ischemia-reperfusion injury.
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