Pan-neuraminidase inhibiting antibodies
The present invention relates to antibodies against influenza neuraminidase, compositions containing the antibodies and methods of using the antibodies.
1 . An antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment comprises:
(a) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of GFKFDDYAM (SEQ ID NO:13); a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of SWGDYTRGPEPKITWY (SEQ ID NO:14), and
a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of GIDGYL (SEQ ID NO:15); a CDR-L2 comprising the amino acid sequence of SLL; and a CDR-L3 comprising the amino acid sequence of LDSYPLFTF (SEQ ID NO:16);
(b) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of GFTFDDYGM (SEQ ID NO: 1); a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of TWGEYTTREEPIHSWY (SEQ ID NO:3), and
a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of DISSFL (SEQ ID NO:8); a CDR-L2 comprising the amino acid sequence of SLL; and
a CDR-L3 comprising the amino acid sequence of LNSYPLFTF (SEQ ID NO:6); or
(c) a heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence of GFTFDDYGM (SEQ ID NO: 1); a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of TWGDYTTGEEIINSWY (SEQ ID NO:10), and
a light chain variable region comprising a CDR-L1 comprising the amino acid sequence of DISSYL (SEQ ID NO:11); a CDR-L2 comprising the amino acid sequence of SLL; and a CDR-L3 comprising the amino acid sequence of LKSYPLFTF (SEQ ID NO:12).
2 . The antibody or antigen-binding fragment of claim 1 , wherein
the heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence of GFKFDDYAM (SEQ ID NO:13) a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of SWGDYTRGPEPKITWY (SEQ ID NO:14), and
the light chain variable region comprises a CDR-L1 comprising the amino acid sequence of GIDGYL (SEQ ID NO:15): a CDR-L2 comprising the amino acid sequence of SLL; and a CDR-L3 comprising the amino acid sequence of LDSYPLFTF (SEQ ID NO:16).
3 . The antibody or antigen-binding fragment of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSGLNWNGDIT AYTDSVKGRFTVSRDNAKNSLYLHINSPKPEDTALYYCARTSSWGDYTRGPEPKITWYF DLWGRGTLVTVSS (SEQ ID NO:44), and the light chain variable region comprises the amino acid sequence of DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAASLLQSGVPSR FSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLFTFGPGTKVDIK (SEQ ID NO:45).
4 . The antibody or antigen-binding fragment of claim 1 , wherein
the heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence of GFTFDDYGM (SEQ ID NO:1): a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of TWGEYTTREEPIHSWY (SEQ ID NO:3), and
the light chain variable region comprises a CDR-L1 comprising the amino acid sequence of DISSFL (SEQ ID NO:8): a CDR-L2 comprising the amino acid sequence of SLL; and a CDR-L3 comprising the amino acid sequence of LNSYPLFTF (SEQ ID NO:6).
5 . The antibody or antigen-binding fragment of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence of EVQLVESGGRVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEFVSGLNWNGDIT AFTDSVKGRFTISRDNAKSSLYLQMNSLRADDTAFYYCARVRTWGEYTTREEPIHSWYF DLWGRGTLVTVSS (SEQ ID NO:40), and the light chain variable region comprises the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQDISSFLAWYQQKPGNAPKVLIYAASLLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQLNSYPLFTFGPGTKVDIK (SEQ ID NO:41).
6 . The antibody or antigen binding fragment of claim 1 , wherein
heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence of GFTFDDYGM (SEQ ID NO:1): a CDR-H2 comprising the amino acid sequence of LNWNGDITA (SEQ ID NO:7); and a CDR-H3 comprising the amino acid sequence of TWGDYTTGEEIINSWY (SEQ ID NO:110), and
the light chain variable region comprises a CDR-L1 comprising the amino acid sequence of DISSYL (SEQ ID NO:11): a CDR-L2 comprising the amino acid sequence of SLL; and a CDR-L3 comprising the amino acid sequence of LKSYPLFTF (SEQ ID NO:12).
7 . The antibody or antigen binding fragment of claim 6 , wherein the heavy chain variable region comprises the amino acid sequence of EVQLVESGGRVVRPGGSLRLSCAASGFTFDDYGMSWVRQPPGKGLEFVSGLNWNGDIT AFTDSVKGRFTISRDNVKSSLYLQMNSLRADDTAFYYCARVRTWGDYTTGEEIINSWYF DLWGRGTLVTVSS (SEQ ID NO:42), and the light chain variable region comprises the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQDISSYLAWYQQKPGNAPKLLIYAASLLQSGVPSR FSAFGSGTEFTLTISSLQPEDFATYYCQHLKSYPLFTFGPGTKVDIK (SEQ ID NO:43).
8 . The antibody or antigen-binding fragment of claim 2 , comprising a heavy chain variable region comprising an amino acid sequence having at least 90% identity to SEQ ID NO:44, and a light chain variable region comprising an amino acid sequence having at least 90% identity to SEQ ID NO:45.
9 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment binds an influenza virus.
10 . The antibody or antigen-binding fragment of claim 9 , wherein the antibody or antigen-binding fragment specifically binds to a neuraminidase.
11 . The antibody or antigen-binding fragment of claim 10 , wherein the antibody or antigen-binding fragment inhibits the neuraminidase with an IC50 of about 0.0001 μg/ml to about 30 μg/ml.
12 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment is humanized.
13 . The antibody or antigen binding fragment of claim 1 , wherein the antibody or antigen binding fragment is a monoclonal antibody and/or is an IgG antibody.
14 . The antibody or antigen bind fragment of claim 1 , wherein the antibody or antigen bind fragment comprises a hinge region or Fc region that contains at least one amino acid substitution, deletion, or insertion relative to the sequence of a wild-type hinge region or a wild-type Fc region, and wherein the substitution, deletion, or insertion prevents or reduces recycling of the antibody or antigen-binding fragment.
15 . A nucleic acid comprising a nucleotide sequence encoding the heavy chain variable region and/or the light chain variable region of the antibody or antigen-binding fragment of claim 1 .
16 . An expression vector comprising the nucleic acid of claim 15 .
17 . A host cell comprising the expression vector of claim 16 .
18 . A vaccine comprising an antibody or antigen-binding fragment of claim 1 .
19 . A pharmaceutical composition, comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier or excipient.
20 . The nucleic acid of claim 15 , comprising the nucleotide sequence of SEQ ID NO:47 and/or the nucleotide sequence of SEQ ID NO:51.