Polynucleotide conjugates comprising PLN-targeting anti-transferrin receptor antibodies and method of use thereof to treat PLN-associated cardiomyopathies
AssigneeAtrium Therapeutics, Inc.
InventorsCecilia Hurtado, Georgios Karamanlidis, Sami Abdulwahab Abdulkadir, Subbarao Nallagatla, Maryam Jordan
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Abstract
Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods of use for antibody-PLN targeting oligonucleotide conjugates (AOC).
Claims24
A polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that mediates the downregulation of PLN mRNA expression levels in a cardiac muscle cell, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions selected from 216-244 of a PLN mRNA comprising an Arg14del (R14del) mutation, wherein the polynucleotide is a double-stranded RNA molecule.
A polynucleotide molecule for modulating PLN mRNA expression levels, wherein the polynucleotide molecule comprises a nucleic acid sequence selected from SEQ ID NOs:
- 302-310 and 330-338, and wherein the polynucleotide molecule is a double-stranded RNA molecule.
A conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide molecule that decreases PLN mRNA expression levels in a cardiac muscle cell, wherein the anti-transferrin receptor antibody or antigen-binding fragment thereof comprises a VH sequence of SEQ ID NO:
- 376, 377, 378, 379, or 380, and a VL sequence of SEQ ID NOs:
- 381, 382, 383, 384, or 385, and wherein the polynucleotide molecule comprises a guide strand having a nucleic acid sequence selected from SEQ ID NOs:
- 302-310 and 330-338 and a passenger strand having a nucleic acid sequence selected from SEQ ID NOs:
- 316-324 and 346-354.
A method of treating a cardiomyopathy associated with PLN mutation in a subject in need thereof, comprising administering to said subject a polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen-binding fragment thereof conjugated to a polynucleotide that mediates the downregulation of PLN mRNA expression levels in a cardiac muscle cell, wherein the polynucleotide hybridizes to a nucleic acid sequence at positions selected from 216-244 of a PLN mRNA, thereby treating cardiomyopathy in said subject, wherein the PLN mutation is an Arg14del (R14del) mutation, and wherein the polynucleotide molecule is a double-stranded RNA molecule.
Dependencies are inferred from the claim text.