Search

EP-4735051-A1 - COMPOSITIONS AND METHODS OF USING PLN-TARGETING ANTIBODY-OLIGONUCLEOTIDE CONJUGATES

EP4735051A1EP 4735051 A1EP4735051 A1EP 4735051A1EP-4735051-A1

Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods of use for antibody- PLN targeting oligonucleotide conjugates (AOC).

Inventors

  • HURTADO, Cecilia
  • KARAMANLIDIS, Georgios
  • ABDULKADIR, Sami Abdulwahab
  • NALLAGATLA, Subbarao
  • JORDAN, Maryam

Assignees

  • Atrium Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. CLAIMS WHAT IS CLAIMED IS: 1. A polynucleotide conjugate comprising an anti-transferrin receptor antibody or antigen- binding fragment thereof conjugated to a polynucleotide that hybridizes to a target sequence of PLN mRNA and mediates RNA interference against PLN mRNA in a muscle cell.
  2. 2. The polynucleotide conjugate of claim 1, wherein the target sequence of the PLN mRNA is a genetic PLN variant.
  3. 3. The polynucleotide conjugate of claim 2, wherein the genetic PLN variant comprises a genetic mutation selected from Arg14del (R14del), Arg9Cys (R9C), and Arg25Cys (R25C).
  4. 4. The polynucleotide conjugate of any one of claim 1-3, wherein the polynucleotide hybridizes to at least 8 contiguous bases of the target sequence of the PLN mRNA.
  5. 5. The polynucleotide conjugate of any one of claims 1-4, wherein the polynucleotide is from about 8 to about 50 nucleotides in length or from about 10 to about 30 nucleotides in length.
  6. 6. The polynucleotide conjugate of any one of claims 1-5, wherein the polynucleotide is a single-stranded antisense polynucleotide or a double-stranded polynucleotide.
  7. 7. The polynucleotide conjugate of claim 6, wherein the single-stranded antisense polynucleotide is an antisense oligonucleotide (ASO).
  8. 8. The polynucleotide conjugate of claim 7, wherein the ASO comprises a nucleic acid sequence having at least 80%, 85%, 90%, 95%, or 100% homology with a sequence selected from SEQ ID NOs: 265-276.
  9. 9. The polynucleotide conjugate of claim 7, wherein the ASO comprises a nucleic acid sequence having at least 14, 15, 16, 17, or 18 consecutive nucleotides from a sequence selected from SEQ ID NOs: 265-276, with no more than 1, 2, or 3 mismatches.
  10. 10. The polynucleotide conjugate of claim 7, wherein the ASO comprises a nucleic acid sequence selected from SEQ ID NOs: 265-276.
  11. 11. The polynucleotide-antibody conjugate of claim 2, wherein the double-stranded polynucleotide is a small interfering RNA (siRNA) comprising a guide strand and a passenger strand.
  12. 12. The polynucleotide conjugate of claim 11, wherein the passenger strand comprises a nucleic acid sequence having at least 80%, 85%, 90%, 95%, or 100% homology with a sequence selected from SEQ ID NOs: 133-264, 314-327, 344-359.
  13. 13. The polynucleotide conjugate of claim 11 or claim 12, wherein the guide strand of comprises a nucleic acid sequence having at least 80%, 85%, 90%, 95%, or 100% homology with a sequence selected from SEQ ID NOs: 1-132, 300-313, 328-343.
  14. 14. The polynucleotide conjugate of claim 11, wherein the passenger strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from SEQ ID NOs: 133-264, 314-327, 344-359, with no more than 1, 2, or 3 mismatches.
  15. 15. The polynucleotide conjugate of claim 11 or claim 12, wherein the guide strand comprises a nucleic acid sequence having at least 16, 17, 18, 19, 20, or 21 consecutive nucleotides from a sequence selected from SEQ ID NOs: 1-132, 300-313, 328-343, with no more than 1, 2, or 3 mismatches.
  16. 16. The polynucleotide conjugate of any one of claims 11-15, wherein the guide strand comprises a nucleic acid sequence of SEQ ID NOs: 37, 49, 74, and the passenger strand comprises a nucleic acid sequence of SEQ ID NOs:169, 181, 206.
  17. 17. The polynucleotide conjugate of claim 1, wherein the polynucleotide comprises at least one 2’ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.
  18. 18. The polynucleotide conjugate of claim 17, wherein the at least one 2’ modified nucleotide comprises: 2’-O-methyl, 2’-O-methoxyethyl (2’-O-MOE), 2’-O-aminopropyl, 2’-deoxy, 2’-deoxy- 2’-fluoro, 2’-O-aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’- O-dimethylaminopropyl (2’-O-DMAP), 2’-O- dimethylaminoethyloxyethyl (2’-O- DMAEOE), or 2’-O-N-methylacetamido (2’-O-NMA) modified nucleotide; comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA); or comprises a combination thereof.
  19. 19. The polynucleotide conjugate of claim 17, wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.
  20. 20. The polynucleotide conjugate of any one of claims 1-19, wherein the polynucleotide comprises a 5’-terminal vinylphosphonate modified nucleotide.

Description

COMPOSITIONS AND METHODS OF USING PLN-TARGETING ANTIBODY- OLIGONUCLEOTIDE CONJUGATES CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 63/511,450 filed June 30, 2023, which is incorporated herein by reference in its entirety. BACKGROUND OF THE DISCLOSURE [0002] Gene suppression by RNA-induced gene silencing provides several levels of control: transcription inactivation, small interfering RNA (siRNA)-induced mRNA degradation, and siRNA-induced transcriptional attenuation. In some instances, RNA interference (RNAi) provides long lasting effects over multiple cell divisions. As such, RNAi represents a viable method useful for drug target validation, gene function analysis, pathway analysis, and disease therapeutics. [0003] Cycling of calcium is the underlying basis of cardiac function and is commonly dysregulated in several forms of cardiac diseases. Altered calcium homeostasis results in arrhythmias and heart failure, which are lead causes of sudden death and cardiac transplantation. [0004] Phospholamban (PLN) functions as a natural reversible inhibitor of calcium cycling in cardiomyocytes, via inhibition of the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump. PLN binding to SERCA reduces SERCA affinity for calcium, which results in depressed cardiac contraction and slower rate of relaxation. As such, exacerbated activity of PLN is associated with cardiac diseases, which are caused by low SERCA expression levels or by super-inhibitory effect of PLN on SERCA associated with PLN mutations. The reduction of PLN expression levels in the heart could therefore be used as a therapeutic approach to restore calcium homeostasis and improve cardiac function. [0005] A number of PLN mutations have been described to result in cardiomyopathies. PLN Arg14del (R14del) causes arrhythmogenic and dilated cardiomyopathy and is of high prevalence in the population of Dutch descent. R14del is the most prevalent disease variant of the PLN gene. Disease onset commonly occurs in middle age and is characterized by severe ventricular arrhythmias and/or ventricular dilation that progresses rapidly to heart failure. Traditional anti- arrhythmic and heart failure medications proved ineffective in the R14del patient population, requiring most carriers to receive an implantable cardioverter-defibrillator to mitigate the risk of sudden cardiac death. As heart failure progresses, patients often need to be placed under cardiac mechanical support and eventually require cardiac transplantation. [0006] Current understanding of the PLN R14del disease suggests that the mutant protein acts as a toxic peptide that affects calcium signaling, proteostasis, and cardiac metabolism. Antibody oligonucleotide conjugates offer promising therapeutic potential by reducing the expression of the mutant PLN. Antibody oligonucleotide conjugates can target regions outside the mutated area, thereby reducing both wild-type and mutant alleles, or they can be specifically designed to target the mutated region with the aim of preferentially knocking down the mutant transcript. All carriers of this mutation identified to date are heterozygous, having one wild-type and one R14del PLN allele. [0007] Other PLN mutations include Arg9Cys (R9C) and Arg25Cys (R25C) and these mutations are gain of function mutations associated with expression of toxic PLN protein. In addition, cardiomyopathy associated with PLN includes dilated cardiomyopathy associated with TTN, LMNA, RI3M20, SCN5A, MYH7, TNNT2, and TPMI mutations. [0008] Furthermore, cardiomyopathy associated with PLN includes hypertrophic cardiomyopathy associated with MYH7, MYBPC3, TNNT2, TNNC, and TPM1 mutations. Hypertrophic cardiomyopathy affects 1 in 500 individuals. Approximately 50% of the cases are monogenic disorders due to mutations of sarcomere proteins that cause increased myofilament calcium sensitivity. Mutant hearts show characteristic diastolic dysfunction and develop hypertrophy. Thickening of the interventricular septum can result in outflow tract obstruction, leading to disease symptoms. [0009] Current treatments that include standard heart failure and antiarrhythmic treatment, pacemaker, defibrillator implantation and surgical ablation, may alleviate the symptoms but cannot be effective treatment to the cardiac diseases caused by genetic abnormalities of PLN gene. However, there are no specific treatments available that target PLN. There is a need to develop therapeutics for treating cardiomyopathy associated with PLN. INCORPORATION BY REFERENCE [0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. SUMMARY OF THE DISCLOSURE [0011] In the present disclosure, methods and compositions of antibody-oligonucleotide conjugates (AOC