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 .- 54 . (canceled)
55 . 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;
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.
56 . The heteromultimer according to claim 55 , wherein the first segment of albumin and the second segment of albumin form a complementary pair of transporter polypeptides.
57 . The heteromultimer according to claim 56 , wherein first transporter polypeptide and the second transporter polypeptide are derived from a mammalian albumin.
58 . The heteromultimer according to claim 57 , wherein the first transporter polypeptide and the second transporter polypeptide are derived from the same type of albumin.
59 . The heteromultimer according to claim 58 , wherein the mammalian albumin is human serum albumin or variant thereof or an alloalbumin or variant thereof.
60 . The heteromultimer according to claim 57 , wherein the transporter polypeptides are derived from different albumins.
61 . The heteromultimer according to claim 57 , 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.
62 . The heteromultimer according to claim 57 , wherein the at least one cargo polypeptide is an antibody, or a fragment or variant thereof.
63 . The heteromultimer according to claim 62 , wherein the antibody is a bispecific antibody, a multispecific antibody, or a therapeutic antibody.
64 . The heteromultimer of claim 63 , wherein the therapeutic antibody binds a cancer antigen.
65 . A pharmaceutical composition comprising the heteromultimer according to claim 55 , and a pharmaceutically acceptable carrier.
66 . One or a combination of two or more nucleic acids encoding the heteromultimer according to claim 55 .
67 . One or more vectors comprising the nucleic acids according to claim 66 .
68 . A host cell comprising nucleic acid encoding the heteromultimer according to claim 55 .
69 . A method of expressing a heteromultimer in cells, the method comprising:
a) transfecting at least one cell with the nucleic acids according to claim 66 , to produce at least one transfected cell; and
b) culturing the at least one transfected cell under conditions suitable for expressing the heteromultimer.
70 . A method of treating a disease in a subject, comprising administration of an effective amount of the heteromultimer according to claim 55 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.
71 . A method of making the heteromultimer according to claim 55 , comprising segmenting the albumin to obtain polypeptides such that the polypeptides self-assemble to form the heteromultimer.
72 . A method of making the heteromultimer according to claim 55 , comprising culturing the host cell of claim 68 such that the nucleic acid encoding the heteromultimer is expressed, and recovering the heteromultimer from the cell culture.