US 2022/0089683 A1 · BI-AND TRI-FUNCTIONAL FUSION PROTEINS AND USES THEREOF

Abstract

Disclosed herein are bi- and tri-functional fusion proteins comprising two or more of an activin antagonist domain, a TOPβ antagonist domain, and an immune checkpoint antagonist domain. In addition, the disclosure provides methods of treating cancer, a tumor, a pre-neoplastic disorder, a hyperproliferative disorder, or a dysplastic disorder comprising administering a bi- or tri-functional fusion protein comprising two or more of an activin antagonist domain, a TOPβ antagonist domain, and an immune checkpoint antagonist domain. Optionally, such methods further comprise administering an additional active agent or supportive therapy for treating the cancer, a tumor, a pre-neoplastic disorder, a hyperproliferative disorder, or a dysplastic disorder.

Claims105

Dependent claims

A fusion protein comprising two or more domains selected from an activin antagonist domain, a TGFβ antagonist domain, and an immune checkpoint antagonist domain.

The fusion protein of any preceding claim, wherein the fusion protein further comprises a polypeptide domain that is heterologous to the activin antagonist domain, TGFβ antagonist domain, and/or immune checkpoint antagonist domain.

The fusion protein of any preceding claim, wherein the fusion protein further comprises a linker domain.

The fusion protein of any preceding claim, wherein the domains of the fusion protein are arranged in an order selected from the group consisting of:

a. A-X-T;
b. A-X-I;
c. T-X-I;
d. A-X-H-X-T;
e. A-X-H-X-I;
f. I-X-H-X-T;
g. A-X-T-X-I;
h. T-X-A-X-I;
i. A-X-I-X-T;
j. A-X-T-H-X-I;
k. T-X-A-H-X-I;
l. A-X-I-H-X-T;
m. A-X-H-T-X-I;
n. T-X-H-A-X-I;
and
o. A-X-H-I-X-T,
wherein (i) “A” corresponds to an activin antagonist domain;
(ii) “T” corresponds to a TGFβ antagonist domain;
(iii) “I” corresponds to an immune checkpoint antagonist domain;
(iv) “H” corresponds to a polypeptide domain that is heterologous to the activin antagonist domain, TGFβ antagonist domain, and immune checkpoint antagonist domains;
and (v) “X” corresponds to an optional linker domain;
and wherein the arrangement of the domains is either N-terminus to C-terminus or C-terminus to N-terminus.

19 more elements

A homodimer comprising the fusion protein of any of the preceding claims.

A heterodimer comprising two or more polypeptide domains selected from an activin antagonist domain, a TGFβ antagonist domain, and an immune checkpoint antagonist domain.

The heterodimer of any preceding claim, wherein the heterodimer further comprises one or more linker domains.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the TGFβ antagonist domain is a TβRII polypeptide.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the heterologous portion comprises a first or second member of an interaction pair.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the linker is between 10 and 25 amino acids in length.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the fusion protein, homodimer or heterodimer comprises one or more modified amino acid residues selected from:

a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the fusion protein, homodimer or heterodimer is isolated.

The fusion protein, homodimer or heterodimer of any preceding claim, wherein the fusion protein, homodimer or heterodimer is recombinant.

The fusion protein, homodimer, or heterodimer of any preceding claim, wherein the immune checkpoint antagonist domain is an antibody selected from ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, or antigen-binding fragment thereof.

A pharmaceutical preparation comprising the fusion protein, homodimer or heterodimer of any preceding claim and a pharmaceutically acceptable excipient.

Dependencies are inferred from the claim text.

Bi-and tri-functional fusion proteins and uses thereof

Life of this patent

Bi-and tri-functional fusion proteins and uses thereof

Life of this patent

Abstract

Claims105