Coiled coil immunoglobulin fusion proteins and compositions thereof
Disclosed herein are immunoglobulin fusion proteins comprising a first antibody region, a first therapeutic agent, and a first connecting peptide; wherein the first therapeutic agent is attached to the first antibody region by the connecting peptide; and wherein the connecting peptide does not comprise a region having beta strand secondary structure. The connecting peptide may comprise an extender peptide. The extender peptide may have an alpha helical secondary structure. The connecting peptide may comprise a linker peptide. The linker peptide may not comprise any secondary structure. Also disclosed herein are compositions comprising the immunoglobulin fusion proteins and methods for using the immunoglobulin fusion proteins for the treatment or prevention of a disease or condition in a subject.
1. An immunoglobulin fusion protein comprising a human or humanized antibody domain, a first therapeutic agent, a first extender peptide comprising a first alpha helical secondary structure, and a second extender peptide comprising a second alpha helical secondary structure; wherein the first extender peptide and the second extender peptide form an anti-parallel coiled coil; and wherein the first extender peptide, the first therapeutic agent, and the second extender peptide are positioned within the antibody domain, and the first therapeutic agent is positioned between the first extender peptide and the second extender peptide.
2. The immunoglobulin fusion protein of claim 1 , further comprising a second therapeutic agent.
3. The immunoglobulin fusion protein of claim 1 , wherein the first extender peptide, the first therapeutic agent, and the second extender peptide replace a portion of a light chain of the antibody domain or a portion of a heavy chain of the antibody domain.
4. The immunoglobulin fusion protein of claim 1 , wherein the antibody domain comprises an amino acid sequence selected from any one of SEQ ID NOs: 19-36 and 271-273, and wherein the first extender peptide, the first therapeutic agent, and the second extender peptide replace a portion of a light chain of the antibody domain or a portion of a heavy chain of the antibody domain.
5. The immunoglobulin fusion protein of claim 1 , wherein the first antibody domain comprises an amino acid sequence selected from amino acid sequences at least 90% homologous to any one of SEQ ID NOs: 19-36 and 271-273, and wherein the first extender peptide, the first therapeutic agent, and the second extender peptide replace a portion of a light chain of the antibody domain or a portion of a heavy chain of the antibody domain.
6. The immunoglobulin fusion protein of claim 1 , wherein the antibody domain comprises a trastuzumab antibody or antigen binding fragment thereof, and wherein the first extender peptide, the first therapeutic agent, and the second extender peptide replace a portion of a light chain of the trastuzumab antibody or antigen binding fragment thereof or a portion of a heavy chain of the trastuzumab antibody or antigen binding fragment thereof.
7. The immunoglobulin fusion protein of claim 1 , wherein the first antibody domain comprises a palivizumab antibody or antigen binding fragment thereof, and wherein the first extender peptide, the first therapeutic agent, and the second extender peptide replace a portion of a light chain of the palivizumab antibody or antigen binding fragment thereof or a portion of a heavy chain of the palivizumab antibody or antigen binding fragment thereof.
8. The immunoglobulin fusion protein of claim 1 , further comprising a second antibody domain.
9. The immunoglobulin fusion protein of claim 1 , wherein
a) the first antibody domain comprises trastuzumab or an antigen binding fragment thereof; and
b) the first therapeutic agent comprises an elafin peptide.
10. The immunoglobulin fusion protein of claim 9 , wherein the first extender peptide, the elafin peptide, and the second extender peptide replace a portion of a trastuzumab heavy chain.
11. The immunoglobulin fusion protein of claim 9 , wherein:
a) a light chain of trastuzumab is represented by an amino acid sequence at least 90% homologous to SEQ ID NOS: 19;
b) an amino terminal region of a heavy chain of trastuzumab is represented by an amino acid sequence at least 90% homologous to SEQ ID NO: 23;
c) a carboxy terminal region of a heavy chain of trastuzumab is represented by an amino acid sequence at least 90% homologous to SEQ ID NO: 24; and
d) the elafin peptide is represented by an amino acid sequence of SEQ ID NO: 258, or an amino acid sequence at least 90% homologous to SEQ ID NO: 258,
wherein the elafin peptide is grafted between the amino terminal region of the heavy chain of trastuzumab and the carboxy terminal region of the heavy chain of trastuzumab to produce a trastuzumab heavy chain fusion that pairs with the light chain of trastuzumab.
12. The immunoglobulin fusion protein of claim 9 , comprising a polypeptide represented by a sequence that is at least 90% homologous to SEQ ID NO: 85.
13. The immunoglobulin fusion protein of claim 1 , wherein the antibody domain comprises a variable domain.