Neutralizing anti-influenza binding molecules and uses thereof
Binding molecules, including bispecific antibodies that include at least two anti-influenza binding domains are disclosed, including binding molecules having a first binding domain that specifically binds influenza A virus and a second binding domain that specifically binds influenza B virus.
1. An isolated binding molecule which specifically binds to influenza A virus and influenza B virus, comprising:
(a) a first binding domain comprising an Fv domain of a first antibody that is capable of binding to influenza A virus hemagglutinin (HA) and neutralizing at least one group 1 subtype and at least 1 group 2 subtype of influenza A virus, wherein the first antibody comprises a VH and a VL selected from:
(i) a VH of SEQ ID NO.: 7 and a VL of SEQ ID NO.: 2; and
(ii) a VH of SEQ ID NO.: 17 and a VL of SEQ ID NO.: 12; and
(b) a second binding domain comprising an scFv of a second antibody that is capable of binding to influenza B virus hemagglutinin (HA) and neutralizing influenza B virus in at least two phylogenetically distinct lineages, wherein the second antibody comprises a VH and a VL selected from:
(i) a VH of SEQ ID NO.: 27 and a VL of SEQ ID NO.: 22;
(ii) a VH of SEQ ID NO.: 33 and a VL of SEQ ID NO.: 32;
(iii) a VH of SEQ ID NO.: 36 and a VL of SEQ ID NO.: 35;
(iv) a VH of SEQ ID NO.: 43 and a VL of SEQ ID NO.: 38;
(v) a VH of SEQ ID NO.: 49 and a VL of SEQ ID NO.: 48;
(vi) a VH of SEQ ID NO.: 52 and a VL of SEQ ID NO.: 51;
(vii) a VH of SEQ ID NO.: 59 and a VL of SEQ ID NO.: 54; and
(viii) a VH of SEQ ID NO.: 65 and a VL of SEQ ID NO.: 64.
2. The isolated binding molecule according to claim 1 , wherein the first binding domain is capable of neutralizing one or more influenza A virus group 1 subtypes selected from: H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18; and one or more influenza A virus group 2 subtypes selected from: H3, H4, H7, H10, H14 and H15.
3. The isolated binding molecule according to claim 1 , wherein the second binding domain is capable of neutralizing influenza B virus in both Yamagata and Victoria lineages.
4. The isolated binding molecule according to claim 1 , wherein the binding molecule is a bispecific antibody.
5. The isolated binding molecule according to claim 1 , wherein the Fv domain of the first binding domain comprises a heavy chain (HC) comprising a polypeptide chain having an amino terminus and a carboxy terminus and a light chain (LC) comprising a polypeptide chain having an amino terminus and a carboxy terminus, and
(a) the second binding domain is covalently linked to the carboxy-terminus of the HC of the first binding domain;
(b) the second binding domain is covalently linked to the amino-terminus of the HC of the first binding domain;
(c) the second binding domain is covalently linked to the amino-terminus of the LC of the first binding domain; or
(d) the second binding domain is covalently intercalated in the polypeptide chain of the HC of the first binding domain.
6. An isolated polynucleotide comprising a nucleic acid which encodes the isolated binding molecule according to claim 1 .
7. A vector comprising the polynucleotide of claim 6 .
8. A host cell comprising the polynucleotide of claim 6 .
9. A composition comprising the isolated binding molecule according to claim 1 and a pharmaceutically acceptable carrier.
10. A method for manufacturing an isolated binding molecule according to claim 1 , comprising culturing a host cell under conditions suitable for expression of the binding molecule.
11. A method for prophylaxis or treatment of influenza A infection, influenza B infection, or a combination thereof in a subject comprising administering an effective amount of an isolated binding molecule according to claim 1 to the subject.