Multivalent heteromultimer scaffold design and constructs
Provided herein are multifunctional heteromer proteins. In specific embodiments is a heteromultimer that comprises: at least two monomeric proteins, wherein each monomeric protein comprises at least one cargo polypeptide, attached to a transporter polypeptide, such that said monomeric proteins associate to form the heteromultimer. These therapeutically novel molecules comprise monomers that function as scaffolds for the conjugation or fusion of therapeutic molecular entities resulting in the creation of bispecific or multivalent molecular species.
1. A heteromultimer comprising:
(i) a first monomeric protein that comprises a first transporter polypeptide comprising a first segment of albumin, and at least one cargo polypeptide, and
(ii) a second monomeric protein that comprises a second transporter polypeptide comprising a second segment of albumin, and at least one cargo polypeptide;
wherein the first segment of albumin and the second segment of albumin are derived from an albumin by segmentation of the albumin, the first transporter polypeptide is different from the second transporter polypeptide, and the transporter polypeptides self-assemble to form a quasi-native albumin structure.
2. The heteromultimer according to claim 1 , wherein the first segment of albumin and the second segment of albumin form a complementary pair of transporter polypeptides.
3. The heteromultimer according to claim 2 , wherein first transporter polypeptide and the second transporter polypeptide are derived from a mammalian albumin.
4. The heteromultimer according to claim 3 , wherein the first transporter polypeptide and the second transporter polypeptide are derived from the same type of albumin.
5. The heteromultimer according to claim 4 , wherein the mammalian albumin is human serum albumin or variant thereof or an alloalbumin or variant thereof.
6. The heteromultimer according to claim 3 , wherein the transporter polypeptides are derived from different albumins.
7. The heteromultimer according to claim 3 , wherein:
a. at least one transporter polypeptide is derived from an alloalbumin;
b. at least one transporter polypeptide is derived from human serum albumin;
c. one of the first transporter polypeptide and the second transporter polypeptide is derived from an alloalbumin and the other is derived from a different alloalbumin, or
d. one of the first transporter polypeptide and the second transporter polypeptide is derived from human serum albumin and the other is derived from an alloalbumin.
8. The heteromultimer according to claim 3 , wherein the first protein comprises at least two different cargo polypeptides and/or the second protein comprises at least two different cargo polypeptides.
9. The heteromultimer according to claim 3 , wherein the first protein and the second protein comprise the same cargo polypeptide.
10. The heteromultimer according to claim 3 , wherein the first protein and the second protein comprise different cargo polypeptides.
11. The heteromultimer according to claim 3 , wherein the at least one cargo polypeptide is an antibody, or a fragment or variant thereof.
12. The heteromultimer according to claim 11 , wherein the antibody is a bispecific antibody, a multi specific antibody, or a therapeutic antibody.
13. The heteromultimer of claim 12 , wherein the therapeutic antibody binds a cancer antigen.
14. A pharmaceutical composition comprising the heteromultimer according to claim 1 , and a pharmaceutically acceptable carrier.
15. One or a combination of two or more nucleic acids encoding the heteromultimer according to claim 1 .
16. One or more vectors comprising the nucleic acids according to claim 15 .
17. A host cell comprising nucleic acid encoding the heteromultimer according to claim 1 .
18. A method of expressing a heteromultimer in cells, the method comprising:
a) transfecting at least one cell with the nucleic acids according to claim 15 , to produce at least one transfected cell; and
b) culturing the at least one transfected cell under conditions suitable for expressing the heteromultimer.
19. A method of treating a disease in a subject, comprising administration of an effective amount of the heteromultimer according to claim 1 to the subject, wherein the disease is selected from an immune disorder, an infectious disease, a cardiovascular disorder, a respiratory disorder, or a metabolic disorder.
20. A method of making the heteromultimer according to claim 1 , comprising segmenting the albumin to obtain polypeptides such that the polypeptides self-assemble to form the heteromultimer.
21. A method of making the heteromultimer according to claim 1 , comprising culturing the host cell of claim 17 such that the nucleic acid encoding the heteromultimer is expressed, and recovering the heteromultimer from the cell culture.