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US 2020/0002407 A1Published application
Antibody neutralizing human respiratory syncytial virus
AssigneeMerck Sharp & Dohme Corp.
InventorsKALPIT A. VORA, KARA S. COX, AIMIN TANG, ZHIFENG CHEN, DANIEL DISTEFANO, LAN ZHANG, HUA-POO SU
Life of this patent
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Abstract
The present invention relates to monoclonal antibodies which have high anti-RSV neutralizing titers. The invention further provides for isolated nucleic acids encoding the antibodies of the invention and host cells transformed therewith. The invention yet further provides for diagnostic, prophylactic and therapeutic methods employing the antibodies and nucleic acids of the invention, particularly as a passive immunotherapy agent in infants and the elderly.
Claims13
1-25. (canceled)
26:
- An antibody or antigen binding fragment that binds a human RSV pre-fusion or human RSV post-fusion F protein epitope comprising at least one amino acid selected from the group consisting of an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) of an F protein having the amino acid sequence set forth in Genbank Accession Number AAR14266,
- wherein the antibody or antigen binding fragment comprises a light chain variable region and a heavy chain variable region, and
- wherein the antibody or antigen binding fragment does not comprise a light chain variable region having the amino acid sequence set forth in SEQ ID NO:8 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9.
27:
- The antibody or antigen binding fragment of claim 26, wherein the epitope comprises an arginine at position 429 (Arg 429) and an isoleucine at position 432 (Iso 432) of the F protein.
28:
- The antibody or antigen binding fragment of claim 26, wherein the epitope comprises an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) of the F protein.
29:
- The antibody or antigen binding fragment of claim 26, wherein the human RSV pre-fusion F protein is a trimer of F protein monomers and when the antibody or antigen binding fragment is bound to the epitope, the light chain of the antibody or antigen binding fragment packs against a glutamic acid at position 161 (Glu 161) and a serine at position 182 (Ser 182) of the neighboring monomer of the RSV pre-fusion trimer of the F protein.
30:
- The antibody or antigen binding fragment of claim 26, wherein the epitope comprises an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) and wherein the human RSV pre-fusion F protein is a trimer of F protein monomers and when the antibody or antigen binding fragment is bound to the epitope, the light chain of the antibody or antigen binding fragment packs against a glutamic acid at position 161 (Glu 161) and a serine at position 182 (Ser 182) of the neighboring monomer of the RSV pre-fusion trimer of the F protein.
31:
- The antibody or antigen binding fragment of claim 26, wherein the antibody or antigen binding fragment
- (i) binds to the human RSV pre-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−12 M as determined by surface plasmon resonance;
- (ii) binds to the human RSV post-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−11 M as determined by surface plasmon resonance;
- or
- (iii) binds to the human RSV pre-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−12 M as determined by surface plasmon resonance and binds to the human RSV post-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−11 M as determined by surface plasmon resonance.
2 more elements
32:
- An antibody or antigen binding fragment that cross-blocks or competes with an isolated antibody RB1 comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO:
- 8 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:
- 9 for binding to an epitope of human RSV pre-fusion or post-fusion F protein F protein having the amino acid sequence set forth in Genbank Accession Number AAR14266,
- wherein the antibody or antigen binding fragment comprises a light chain variable region and a heavy chain variable region, and
- wherein the antibody or antigen binding fragment has at least one of the following characteristics:
- (i) binds to a human RSV pre-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−12 M as determined by surface plasmon resonance;
- (ii) binds to a human RSV post-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−11 M as determined by surface plasmon resonance;
- or
- (iii) binds to a human RSV pre-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−12 M as determined by surface plasmon resonance and binds to a human RSV post-fusion F protein with a Kd value of about 1×10−9 M to about 1×10−11 M as determined by surface plasmon resonance, wherein the antibody or antigen binding fragment that cross-blocks or competes with the isolated antibody RB1 is not the isolated antibody RB1 comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO:
- 8 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:
- 9.
8 more elements
33:
- The antibody or antigen binding fragment of claim 32, wherein the human RSV pre-fusion or post-fusion F protein epitope comprises at least one amino acid selected from the group consisting of an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) of the F protein.
34:
- The antibody or antigen binding fragment of claim 32, wherein the human RSV pre-fusion or post-fusion F protein epitope comprises an arginine at position 429 (Arg 429) and an isoleucine at position 432 (Iso 432) of the F protein.
35:
- The antibody or antigen binding fragment of claim 32, wherein the human RSV pre-fusion or post-fusion F protein epitope comprises an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) of the F protein.
36:
- The antibody or antigen binding fragment of claim 32, wherein the human RSV pre-fusion F protein is a trimer of F protein monomers and when the antibody or antigen binding fragment is bound to the epitope, the light chain of the antibody or antigen binding fragment packs against a glutamic acid at position 161 (Glu 161) and a serine at position 182 (Ser 182) of the neighboring monomer of the RSV pre-fusion trimer of the F protein.
37:
- The antibody or antigen binding fragment of claim 32, wherein the human RSV pre-fusion or post-fusion F protein epitope comprises an asparagine at position 426 (Asn 426), an arginine at position 429 (Arg 429), an isoleucine at position 432 (Iso 432), a lysine at position 433 (Lys 433), and a lysine at position 445 (Lys 445) and wherein the human RSV pre-fusion F protein is a trimer of F protein monomers and when the antibody or antigen binding fragment is bound to the epitope, the light chain of the antibody or antigen binding fragment packs against a glutamic acid at position 161 (Glu 161) and a serine at position 182 (Ser 182) of the neighboring monomer of the RSV pre-fusion trimer of the F protein.