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. An isolated antibody that binds 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,
(iv) (a) 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, (d) 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: 43, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44 and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45,
(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. An isolated antibody, comprising (a) a VH sequence having the amino acid sequence of any one of SEQ ID NOs: 2-6; (b) a VL sequence having the amino acid sequence of any one of SEQ ID NOs: 8-10; or (c) a VH sequence of any one of SEQ ID NOs: 2-6 and a VL sequence of any one of SEQ ID NOs: 7-10.
3. The antibody of claim 1 , 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.
4. The antibody of claim 2 , 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.
5. The antibody of claim 3 , 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):
(a) positions 267, 268, and 324;
(b) positions 236, 267, 268, 324, and 332; and
(c) positions 326 and 333;
according to EU numbering.
6. The antibody of claim 4 , 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):
(d) positions 267, 268, and 324;
(e) positions 236, 267, 268, 324, and 332; and
(f) positions 326 and 333;
according to EU numbering.
7. The antibody of claim 3 , wherein the variant Fc region comprises amino acids selected from the group consisting of:
(a) Glu at position 267;
(b) Phe at position 268;
(c) Thr at position 324;
(d) Ala at position 236;
(e) Glu at position 332;
(f) Ala, Asp, Glu, Met, or Trp at position 326; and
(g) Ser at position 333;
according to EU numbering.
8. The antibody of claim 6 , wherein the variant Fc region comprises amino acids selected from the group consisting of:
(h) Glu at position 267;
(i) Phe at position 268;
(j) Thr at position 324;
(k) Ala at position 236;
(l) Glu at position 332;
(m) Ala, Asp, Glu, Met, or Trp at position 326; and
(n) Ser at position 333;
according to EU numbering.
9. The antibody of claim 3 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(a) Ala at position 434;
(b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(d) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
10. The antibody of claim 4 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(e) Ala at position 434;
(f) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(g) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(h) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
11. The antibody of claim 5 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(i) Ala at position 434;
(j) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(k) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(l) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
12. The antibody of claim 6 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(m) Ala at position 434;
(n) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(o) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(p) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
13. The antibody of claim 7 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(q) Ala at position 434;
(r) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(s) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(t) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
14. The antibody of claim 8 , wherein the variant Fc region further comprises amino acids selected from the group consisting of:
(u) Ala at position 434;
(v) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440;
(w) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; and
(x) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440;
according to EU numbering.
15. An isolated antibody that binds to dengue virus (DENV) E protein, wherein the antibody comprises:
(a) VH comprising the amino acid sequence of SEQ ID NO: 2, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(b) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(c) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 54 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(d) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(e) VH comprising the amino acid sequence of SEQ ID NO: 4, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(f) VH comprising the amino acid sequence of SEQ ID NO: 5, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(g) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 8, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(h) VH comprising the amino acid sequence of SEQ ID NO: 3, VL comprising the amino acid sequence of SEQ ID NO: 9, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(i) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 10, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(j) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 10, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(k) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 46 and CL comprising the amino acid sequence of SEQ ID NO: 60,
(l) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 54 and CL comprising the amino acid sequence of SEQ ID NO: 60, or
(m) VH comprising the amino acid sequence of SEQ ID NO: 6, VL comprising the amino acid sequence of SEQ ID NO: 7, CH comprising the amino acid sequence of SEQ ID NO: 59 and CL comprising the amino acid sequence of SEQ ID NO: 60.