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-11780908-B2
Publication Date
2023-10-10
Expiration Date
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 and polypeptides comprising variant Fc regions. The variant Fc regions include at least one amino acid alteration in a parent Fc region, with the variant having a substantially decreased FcγR-binding activity while not having a substantially decreased C1q-binding activity when compared to the parent Fc region.
A key feature is engineering of the Fc region to reduce FcγR binding activity while maintaining C1q binding via C1q. The described FcγR binding decreases are discussed in relation to Fcγ receptors, including FcγR1a, FcγR2a 167H/167R, FcγR2b, FcγRIIIa 158F/158V, and FcγRIIIb NA1/NA2.
The invention further specifies variant Fc compositions including Ala at positions 234 and 235 in EU numbering and additional amino acid alterations selected from defined position groups. The document also describes recombinant and sequence-related aspects for producing the antibodies or polypeptides, including nucleic acids encoding the antibodies/polypeptides and recombinant production framework/sequence definitions.
Broad characterization approaches are outlined to evaluate antigen binding and interactions of the Fc region, including ELISA and BIACORE/SPR-type binding assays, and characterization of FcR and C1q interactions. Therapeutic and medicament uses are described for treating DENV or a viral infection.
Claims Coverage
The independent claims center on Fc engineering that substantially decreases FcγR binding while not substantially decreasing C1q binding, and on antibody preparation using specific human IgG Fc variant sequences selected from SEQ ID NOs 51-59.
Variant Fc region with decreased FcγR binding while maintaining C1q binding
A polypeptide comprising a variant Fc region comprising at least one amino acid alteration in a parent Fc region, wherein the variant Fc region has a substantially decreased FcγR-binding activity and does not have a substantially decreased C1q-binding activity when compared to the parent Fc region, wherein the variant Fc region comprises Ala at position 234, Ala at position 235 and further amino acid alterations of any one of the following (a)-(c) according to EU numbering.
Preparing an antibody using a human IgG Fc variant sequence selected from SEQ ID NOs 51-59
A process for preparing an antibody comprising combining a VH sequence with a human IgG Fc variant sequence of any one of SEQ ID NOs: 51-59, combining a VL sequence, cloning each one of the combinations in an expression vector, expressing the resulting expression vectors in co-transfected cells, and purifying the resulting antibody from the expressed material.
The inventive coverage is directed to variant Fc polypeptides that reduce FcγR binding without substantially decreasing C1q binding, using specific EU-position amino acid alteration patterns, and to a process for preparing antibodies using human IgG Fc variant sequences selected from SEQ ID NOs 51-59.
Stated Advantages
Substantially decreased FcγR-binding activity compared to the parent Fc region.
Does not have substantially decreased C1q-binding activity compared to the parent Fc region.
Preservation of CDC via C1q binding.
Reduced ADE while preserving CDC.
Designed to avoid antibody-dependent enhancement (ADE) risk by decreasing FcγR binding while maintaining C1q binding.
Documented Applications
Therapeutic use of anti-DENV antibodies and/or immunoconjugates, including in vivo mouse efficacy, and dengue virus targeting broadly including dengue flaviviruses (DENV-1/2/3/4).
Diagnostics/detection applications using the described antibodies/polypeptides.
Pharmaceutical formulations of the polypeptides with a pharmaceutically acceptable carrier.
Therapeutic and medicament uses for treating dengue virus (DENV) or a viral infection using the described anti-DENV antibodies/polypeptides.
Characterization/application of binding assessment using ELISA and BIACORE/SPR-type assays to evaluate antigen binding and FcR/C1q interactions.
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