Bispecific antibodies and fusion proteins that bind to EBOV and NPC1
Disclosed are bispecific antibodies and bispecific fusion constructs that bind to Niemann-Pick CI (NPC1) receptor for treating or preventing filovirus infections, pharmaceutical compositions comprising the bispecific antibodies, and therapeutic methods using the bispecific antibodies.
1. A monoclonal antibody or fragment thereof that binds to Niemann-Pick C1 (NPC1) receptor, the antibody or fragment thereof comprising
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. A bispecific antibody or a 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 bispecific antibody or a bispecific fusion construct of claim 2 , wherein a NPC1-specific sequence is fused to a single-chain variable fragment (scFv) sequence derived from monoclonal antibody KZ52.
4. The bispecific antibody or a bispecific fusion construct of claim 3 , wherein fusion is to a N- or C-terminus of an IgG heavy chain or light chain.
5. The bispecific antibody or a bispecific fusion construct 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.
6. The bispecific antibody or a bispecific fusion construct of claim 2 , wherein the bispecific antibody comprises the amino acid sequence set forth in any one of SEQ ID NOs:9-20.
7. The bispecific antibody or a bispecific fusion construct of claim 2 , wherein the Ebola virus is Zaire ebolavirus.
8. A fusion construct comprising the antibody or fragment of claim 1 fused to Niemann-Pick C2 (NPC2).
9. The fusion construct of claim 8 , wherein the fusion construct comprises the amino acid sequence set forth in SEQ ID NO:21 or SEQ ID NO:22.