Anti-dengue virus antibodies, polypeptides containing variant Fc regions, and methods of use
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.
1. A pharmaceutical composition comprising an isolated antibody that binds to dengue virus (DENV) E protein, wherein the antibody comprises:
(i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(v) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28;
(vi) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29;
(vii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30; or
(viii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.
2. A method of treating an individual having a DENV infection, comprising administering to the individual in need thereof an effective amount of the pharmaceutical composition of claim 1 .
3. An isolated polynucleotide encoding an antibody that binds to dengue virus (DENV) E protein, wherein the antibody comprises:
(i) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(ii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(iv) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27;
(v) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28;
(vi) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29;
(vii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30; or
(viii) (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27.
4. A host cell comprising the polynucleotide of claim 3 .
5. A method of producing an antibody comprising culturing the host cell of claim 4 so that the antibody is produced.
6. A method of detecting the presence of DENV and/or DENV E protein in a biological sample using the pharmaceutical composition of claim 1 .
7. A method of selecting subjects eligible for therapy with an anti-DENV antibody using the pharmaceutical composition of claim 1 , wherein DENV or DENV E protein is a biomarker of selection for patients.
8. A method of treating an individual having a DENV infection, comprising administering to the individual in need thereof an effective amount of the pharmaceutical composition of claim 1 , further comprising administering to the individual an effective amount of at least one additional therapeutic agent.
9. A method of blocking binding of DENV E protein to and/or DENV entry into a host cell, comprising administering to the individual in need thereof an effective amount of the pharmaceutical composition of claim 1 .
10. 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 FcgR-binding activity and does not have a substantially decreased C1q-binding activity when compared to the parent Fc region.
11. The polypeptide of claim 10 , comprising the amino acid sequence of any one of SEQ ID NOs: 51-59.