US 12,497,437 B2 · Modified Mullerian Inhibiting Substance (MIS) proteins and uses thereof for the treatment of diseases

Abstract

The present invention relates to modified recombinant human MIS protein which has improved cleavage and increased bioactivity and increased potency as compared to wild-type human MIS protein. Other aspects of the invention relate to methods to prevent and treat cancers, such as cancers that express the MIS receptor type II (MISRII) by administering to a subject a composition comprising a recombinant human MIS protein. Another aspect of the present invention relates to methods to lower plasma androgen levels in a subject, and/or for the treatment of a subject with a disease characterized by excess androgen. Another aspect provides pharmaceutical compositions and kits and methods for use comprising a recombinant human MIS protein. Another aspect of the present invention relates to methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with the recombinant MIS protein that lowers the effective dose of the chemotherapeutic agent.

Claims19

Dependent claims

A method of manufacturing an isolated recombinant human Mullerian Inhibiting Substance (MIS) homodimer, comprising

a) culturing, under culture media conditions to promote the expression of the recombinant MIS homodimer, a host cell comprising a vector comprising a nucleic acid sequence of SEQ ID NO:
4, or a sequence of at least 95% sequence identity to the nucleic acid sequence of SEQ ID NO:
4, or a nucleic acid sequence having at least 95% sequence identity to nucleotides 79-1680 of SEQ ID NO:
4, where nucleotides 1-78 of SEQ ID NO:
4 are replaced with the nucleic acids encoding a non-MIS leader sequence;
and
b) producing the recombinant MIS homodimer, and
c) harvesting the produced recombinant MIS homodimer,
wherein the recombinant MIS homodimer comprises two monomers, each monomer comprising (i) a N-terminal domain of the recombinant MIS protein comprising amino acid residues 26-451 of SEQ ID NO:
1, wherein residue 450 of SEQ ID NO:
1 is changed from Q to R or a conservative amino acid of R, and (ii) the C-terminal domain of recombinant MIS protein comprising amino acid residues 452-560 of SEQ ID NO:
1, wherein the MIS homodimer does not comprise a FLAG tag.

9 more elements

A heterologous nucleic acid sequence encoding a recombinant human Mullerian Inhibiting Substance (hMIS) protein, the heterologous nucleic acid sequence comprising SEQ ID NO:

4 or a nucleic acid sequence having at least 95% sequence identity to nucleotides 79-1680 of SEQ ID NO:
4, and where nucleotides 1-78 of SEQ ID NO:
4 are replaced with the nucleic acid sequence encoding a non-MIS leader sequence.

Dependencies are inferred from the claim text.

Modified Mullerian Inhibiting Substance (MIS) proteins and uses thereof for the treatment of diseases

Life of this patent

Modified Mullerian Inhibiting Substance (MIS) proteins and uses thereof for the treatment of diseases

Life of this patent

Abstract

Claims19