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

Abstract

The disclosure provides anti-DENV antibodies and methods of making and using the same. Nucleic acids encoding 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 the same. Nucleic acids encoding 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 bind DENV E protein. The antibodies are described as isolated antibody constructs that comprise defined heavy-chain and light-chain variable-region hypervariable loops (HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3), wherein each loop is defined by an amino acid sequence of one or more SEQ ID NOs.

The invention further addresses Fc engineering for the anti-DENV antibodies. A variant Fc region comprising at least one amino acid alteration is described as having substantially decreased FcgR-binding activity while not having a substantially decreased C1q-binding activity when compared with a parent Fc region. The description emphasizes reducing antibody-dependent enhancement risk while preserving CDC (C1q) and antiviral efficacy.

Variant Fc region alterations are described using EU-numbered Fc positions, including positions 234/235 and sets that include 236, 267, 268, 324, 326, 332, and 333, and optionally 428/434/436/438/440. Variant Fc polypeptides are described with specific sequence identifiers (SEQ ID NOs 51-59), together with antibody constructs and assay frameworks using BIACORE/SPR sensorgrams, RU-ratio criteria, and C1q binding ELISA.

Claims Coverage

The provided claims cover two main inventive features: (1) a pharmaceutical composition comprising an isolated anti-DENV E protein-binding antibody defined by specific HVR-H1/H2/H3 and HVR-L1/L2/L3 SEQ ID NOs, and (2) a polypeptide comprising a variant Fc region with substantially decreased FcgR-binding activity while maintaining C1q binding not substantially decreased. The claim set also includes an isolated polynucleotide encoding the defined antibody in one item.

Overall, the claim coverage ties the anti-DENV strategy to antibody variable-region definitions, an isolated polynucleotide encoding that antibody, and Fc-region polypeptides engineered to substantially decrease FcgR-binding activity without substantially decreasing C1q-binding activity.

Stated Advantages

Documented Applications