Methods of treating filovirus infections utilizing bispecific antibodies and fusion proteins that bind EBOV and NPC1
Disclosed are bispecific antibodies and bispecific fusion constructs that bind to Niemann-Pick C1 (NPC1) receptor for treating or preventing filovirus infections, pharmaceutical compositions comprising the bispecific antibodies, and therapeutic methods using the bispecific antibodies.
1. A method of treating or preventing or reducing or inhibiting a filovirus infection in a subject comprising administering to the subject a monoclonal antibody or fragment thereof that binds to Niemann-Pick C1 (NPC1) receptor in an amount effective to treat or prevent or reduce or inhibit a filovirus infection in a subject, wherein the antibody or fragment thereof comprises:
a variable region of a light chain that comprises the amino acid sequence set forth in SEQ ID NO:3 and a variable region of a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:4; or
a variable region of a light chain that comprises the amino acid sequence set forth in SEQ ID NO:5 and a variable region of a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:6; or
a variable region of a light chain that comprises the amino acid sequence set forth in SEQ ID NO:7 and a variable region of a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:8.
2. The method of claim 1 , wherein the monoclonal antibody is provided in a bispecific antibody or bispecific fusion construct comprising (i) the antibody or fragment of claim 1 and (ii) an antibody or fragment that binds to an Ebola virus, wherein the antibody or fragment that binds to the Ebola virus is monoclonal antibody KZ52 or a single-chain variable fragment (scFv) sequence derived from monoclonal antibody KZ52.
3. The method of claim 2 , wherein a NPC1-specific sequence is fused to a single-chain variable fragment (scFv) sequence derived from EBOV GP-specific monoclonal antibody KZ52.
4. The method of claim 3 , wherein fusion is to a N- or C-terminus of an IgG heavy chain or light chain.
5. The method of claim 1 , wherein the monoclonal antibody is provided in a fusion construct comprising the antibody or fragment of claim 1 fused to Niemann-Pick C2 (NPC2).
6. The method of claim 2 , wherein the bispecific antibody comprises heavy and light chains of a NPC1-specific sequence fused to variable VH and VL domains of KZ52 to generate a dual-variable domain Ig.
7. The method of claim 2 , wherein the bispecific antibody comprises the amino acid sequence set forth in any one of SEQ ID NOs:9-20.
8. The method of claim 5 , wherein the bispecific fusion construct comprises the amino acid sequence set forth in SEQ ID NO:21 or SEQ ID NO:22.
9. The method of claim 1 , wherein the subject is infected with a filovirus.
10. The method of claim 1 , wherein the subject is at risk for infection with a filovirus.
11. The method of claim 10 , wherein the subject is a family member or healthcare worker in an area of an outbreak of a filovirus infection.
12. The method of claim 10 , wherein the subject is a medical personnel, first responder or military personnel potentially exposed or exposed to a filovirus as the result of bioterrorism or biological warfare.
13. The method of claim 10 , wherein the subject is a biosafety level 3/4 laboratory personnel or animal worker potentially exposed or exposed to a filovirus.
14. The method of claim 1 , wherein the filovirus is an Ebola virus.
15. The method of claim 14 , wherein the Ebola virus species is Zaire ebolavirus or Sudan ebolavirus.
16. The method of claim 1 , wherein the filovirus is a Marburg virus, a Bundibugyo virus, a Sudan virus, a Ravn virus or a Lloviu virus.
17. The method of claim 1 , wherein the subject is a mammal.
18. The method of claim 1 , wherein the subject is a human.