Anti-dengue virus antibodies, polypeptides containing variant Fc regions, and methods of use
Inventors
Sampei, Zenjiro • KOO, Xing'er Christine • Fink, Katja • ZUEST, Roland
Assignees
Chugai Pharmaceutical Co Ltd • Agency for Science Technology and Research Singapore • Chugai Pharmabody Research Pte Ltd
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Publication Number
US-12187786-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The disclosure provides anti-DENV antibodies and methods of making and using the same. Nucleic acids encoding the anti-DENV antibodies and host cells comprising the nucleic acids are also provided. The anti-DENV antibodies have uses that include treating DENV infection. The disclosure also provided polypeptides containing a variant Fc region and methods of making and using the same. Nucleic acids encoding the polypeptides and host cells comprising the nucleic acids are also provided. The polypeptides have uses that include treating a viral infection. Also claimed is a polypeptide comprising a Fc variant comprising at least one amino acid alteration in a parent Fc region, wherein the variant Fc region has a substantially decreased FcYR-binding activity and does not have a substantially decreased C1 q-binding activity when compared to the parent Fc region.
Core Innovation
The invention relates to anti-dengue virus (DENV) antibodies that target the DENV envelope (E) protein and variant Fc regions engineered to decrease FcγR-binding activity while maintaining C1q-binding activity. The disclosure further defines antibodies by specific HVR sequences, including HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3, with associated SEQ ID NOs, and pairs selected VH and VL variant sequences with selected human IgG1 CH and human CL sequences.
The variant Fc regions are described in the context of avoiding substantially increased FcRn binding activity at pH 7.4 while preserving complement-related activity. The description refers to FcγRs and FcRn, and identifies Fc-amino-acid alterations using EU numbering positions such as 234/235, 267/268, 324, 326, 332, 333, with optional positions including 428/434/436/438/440.
The disclosure also includes isolated nucleic acids, host cells, formulations, and therapeutic use for treating DENV infection and reducing antibody-dependent enhancement risk. It further describes antibodies, Fc fusions, and chimeric or humanized antibodies, with embodiment mappings for different antibody formats and assay frameworks referenced for FcRn binding and C1q binding.
Claims Coverage
Two independent claim themes are presented across the inputs, with a total of five merged inventive features: one centered on defined antibody HVR sequence segments and variable-region pairing, and one centered on preparing antibodies while controlling FcγR-binding activity and preserving C1q-binding activity.
Defined hvr sequence segments for antibody variable regions
The antibody is prepared such that HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprise the amino acid sequences of the specified SEQ ID NOs.
Vh variant and human IgG1 ch pairing
A VH variant sequence selected from SEQ ID NO: 6 (3CH1047) or SEQ ID NO: 95 (3CH1049) is combined with a human IgG1 CH sequence selected from SEQ ID NO: 46 (SG182), SEQ ID NO: 54 (SG1095), or SEQ ID NO: 59 (SG1106).
Vl variant and human cl pairing
A VL variant sequence selected from SEQ ID NO: 7 (3CL) or SEQ ID NO: 98 (3CL633) is combined with a human CL sequence SEQ ID NO: 60 (SK1).
Expression vector cloning and co-transfected cell expression
Each VH/VL combination is cloned in an expression vector, and the resulting expression vectors are expressed in co-transfected cells to produce the antibody.
Purification of the resulting antibody
The antibody produced from expression in co-transfected cells is purified from the resulting expression.
The claim coverage focuses on antibodies with defined HVR sequence segments and selected VH/VL pairing choices, together with cloning, co-transfection, and purification, and on variant Fc-region antibodies that decrease FcγR-binding activity while maintaining C1q-binding activity.
Stated Advantages
Reduced antibody-dependent enhancement risk by decreasing FcγR-mediated effector function while maintaining substantially preserved C1q-binding activity.
Substantially decreased FcγR-binding activity while substantially preserving C1q-binding activity.
Maintaining C1q binding while reducing FcγR binding.
Antiviral efficacy and ADE mitigation as linked objectives.
Avoiding substantially increased FcRn binding activity at pH 7.4.
Documented Applications
Therapeutic use for treating dengue virus (DENV) infection.
Use for reducing antibody-dependent enhancement risk in the context of anti-DENV antibodies.
Use with anti-DENV antibodies and DENV E protein.
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