IP Library › Granted Patent US 12,708,669
Granted Patent B2
US 12,708,669 · App. 19/288,923 · Granted Aug 18, 2026

Polynucleotide conjugates comprising

Inventors: Cecilia Hurtado (San Diego, CA); Georgios Karamanlidis (Thousand Oaks, CA); Sami Abdulwahab Abdulkadir (San Diego, CA); Subbarao Nallagatla (San Diego, CA); Maryam Jordan (Escondido, CA)
Assignee: ATRIUM THERAPEUTICS, INC.
A61K47/549A61K47/6849A61P9/00C12N15/113C12N2310/14C12N2310/315C12N2310/321C12N2310/3231C12N2310/3513
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Quick Facts
Patent No.
US 12,708,669
App. No.
19/288,923
Filed
Aug 1, 2025
Granted
Aug 18, 2026
Kind
B2
Art Unit
1647
USPC
424/181.1
Abstract

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

Claims (24)

1 . 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.

2 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide is a double-stranded small interfering RNA (siRNA) comprising a guide strand and a passenger strand.

3 . The polynucleotide conjugate of claim 2 , 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: 316-324 and 346-354.

4 . The polynucleotide conjugate of claim 2 , 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: 302-310 and 330-338.

5 . The polynucleotide conjugate of claim 3 , wherein the passenger strand comprises a nucleic acid sequence selected from SEQ ID NOs: 316-324 and 346-354.

6 . The polynucleotide conjugate of claim 4 , wherein the guide strand comprises a nucleic acid sequence selected from SEQ ID NOs: 302-310 and 330-338.

7 . 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.

8 . The polynucleotide conjugate of claim 7 , 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), 2′—O—N-methylacetamido (2′-O-NMA) modified nucleotide, locked nucleic acid (LNA), ethylene nucleic acid (ENA), or a combination thereof.

9 . The polynucleotide conjugate of claim 7 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

10 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide comprises a 5′-terminal vinylphosphonate-modified nucleotide.

11 . The polynucleotide conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a non-human antibody or antigen binding fragment thereof, a human antibody or antigen binding fragment thereof, a humanized antibody or antigen binding fragment thereof, a chimeric antibody or antigen binding fragment thereof, a monoclonal antibody or antigen binding fragment thereof, a monovalent Fab′, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or antigen binding fragment thereof.

12 . The polynucleotide conjugate of claim 1 , wherein the polynucleotide conjugate has a polynucleotide to antibody ratio of from about 1 to about 4.

13 . The polynucleotide conjugate of claim 1 , wherein polynucleotide conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the polynucleotide.

14 . 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.

15 . The polynucleotide molecule of claim 14 , wherein the polynucleotide molecule preferentially downregulates an expression level of a mutated PLN mRNA, relative to a wild-type PLN mRNA.

16 . 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.

17 . The conjugate of claim 16 , wherein the passenger strand or the guide strand comprises a 5′-terminal vinylphosphonate-modified nucleotide.

18 . The conjugate of claim 16 , wherein the conjugate comprises a linker connecting the anti-transferrin receptor antibody or antigen-binding fragment thereof to the polynucleotide molecule.

19 . The conjugate of claim 18 , wherein the linker comprises a maleimide group.

20 . The conjugate of claim 16 , wherein the polynucleotide molecule is selected from the group consisting of the guide strand sequence of SEQ ID NO: 302 and the passenger strand sequence of SEQ ID NO: 316; the guide strand sequence of SEQ ID NO: 303 and the passenger strand sequence of SEQ ID NO: 317; the guide strand sequence of SEQ ID NO: 304 and the passenger strand sequence of SEQ ID NO: 318; the guide strand sequence of SEQ ID NO: 331 and the passenger sequence of SEQ ID NO: 347; and the guide strand sequence of SEQ ID NO: 332 and the passenger strand sequence of SEQ ID NO: 348.

21 . 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.

22 . The method of claim 21 , wherein the cardiomyopathy associated with PLN mutation is a dilated cardiomyopathy or a hypertrophic cardiomyopathy.

23 . The method of claim 22 , wherein the dilated cardiomyopathy is a genetic dilated cardiomyopathy associated with one or more mutations selected from TTN, LMNA, RI3M20, SCN5A, MYH7, TNNT2, and TPMI mutations.

24 . The method of claim 22 , wherein the hypertrophic cardiomyopathy is associated with one or more mutations selected from MYH7, MYBPC3, TNNT2, TNNC, and TPM1 mutations.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: AVIDITY BIOSCIENCES, INC.
To: ATRIUM THERAPEUTICS, INC.
Reel/Frame 074143/0954 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 19, 2025
From: HURTADO, CECILIA; KARAMANLIDIS, GEORGIOS; ABDULKADIR, SAMI ABDULWAHAB; NALLAGATLA, SUBBARAO; JORDAN, MARYAM
To: AVIDITY BIOSCIENCES, INC.
Reel/Frame 072063/0873 →
Continuity (3)
Continuation 18759724 · Jun 28, 2024
Provisional Application 63511450 · Jun 30, 2023
Related Publication 20250352651A1 · Nov 20, 2025
References Cited (167)
US 4694778A · Learn et al. · 1987 [cited by applicant]
US 5142047A · Summerton et al. · 1992 [cited by applicant]
US 5334711A · Sproat et al. · 1994 [cited by applicant]
US 5627053A · Usman et al. · 1997 [cited by applicant]
US 5716824A · Beigelman et al. · 1998 [cited by applicant]
US 5736557A · Hofheinz et al. · 1998 [cited by applicant]
US 5889136A · Scaringe et al. · 1999 [cited by applicant]
US 6008400A · Scaringe et al. · 1999 [cited by applicant]
US 6111086A · Scaringe · 2000 [cited by applicant]
US 6821783B1 · Comely et al. · 2004 [cited by applicant]
US 6884869B2 · Senter et al. · 2005 [cited by applicant]
US 7498298B2 · Doronina et al. · 2009 [cited by applicant]
US 7850975B2 · Mullis · 2010 [cited by applicant]
US 8090542B2 · Khvorova et al. · 2012 [cited by applicant]
US 8288352B2 · Doronina et al. · 2012 [cited by applicant]
US 8501930B2 · Rozema et al. · 2013 [cited by applicant]
US 8604184B2 · Mullis et al. · 2013 [cited by applicant]
US 8609105B2 · Senter et al. · 2013 [cited by applicant]
US 8697688B2 · Howard et al. · 2014 [cited by applicant]
US 8936910B2 · Mitsch et al. · 2015 [cited by applicant]
US 9089614B2 · Lin et al. · 2015 [cited by applicant]
US 10550188B2 · Geall et al. · 2020 [cited by applicant]
US 10612027B2 · Maier et al. · 2020 [cited by applicant]
US 10881743B2 · Geall et al. · 2021 [cited by applicant]
US 10913800B2 · Darimont · 2021 [cited by examiner]
US 10994020B2 · Levin et al. · 2021 [cited by applicant]
US 11110180B2 · Geall et al. · 2021 [cited by applicant]
US 11111309B2 · Subramanian · 2021 [cited by examiner]
US 11555190B2 · Malecova et al. · 2023 [cited by applicant]
US 20060148742A1 · Kaye et al. · 2006 [cited by applicant]
US 20080113351A1 · Naito et al. · 2008 [cited by applicant]
US 20130028919A1 · Howard et al. · 2013 [cited by applicant]
US 20130309256A1 · Lyon et al. · 2013 [cited by applicant]
US 20140127239A1 · Howard · 2014 [cited by applicant]
US 20140194610A1 · Verdine et al. · 2014 [cited by applicant]
US 20140286970A1 · Jeffrey et al. · 2014 [cited by applicant]
US 20140294851A1 · Nguyen · 2014 [cited by applicant]
US 20150037360A1 · Smith · 2015 [cited by applicant]
US 20150105539A1 · Miao et al. · 2015 [cited by applicant]
US 20150105540A1 · Miao et al. · 2015 [cited by applicant]
US 20150211006A1 · Butler et al. · 2015 [cited by applicant]
US 20190240346A1 · Sugo et al. · 2019 [cited by applicant]
US 20220008550A1 · Geall et al. · 2022 [cited by applicant]
US 20240401061A1 · Kubli et al. · 2024 [cited by applicant]
US 20250032622A1 · Hurtado et al. · 2025 [cited by applicant]
EP 1579015A2 · 2005 [cited by applicant]
EP 2126084B1 · 2014 [cited by applicant]
WO WO9207065A1 · 1992 [cited by applicant]
WO WO9315187A1 · 1993 [cited by applicant]
WO WO9726270A2 · 1997 [cited by applicant]
WO WO9734631A1 · 1997 [cited by applicant]
WO WO9813526A1 · 1998 [cited by applicant]
WO WO0116312A2 · 2001 [cited by applicant]
WO WO2006096441A2 · 2006 [cited by applicant]
WO WO2009099942A2 · 2009 [cited by applicant]
WO WO2009126933A2 · 2009 [cited by applicant]
WO WO2012177639A2 · 2012 [cited by applicant]
WO WO2013166155A1 · 2013 [cited by applicant]
WO WO2014080251A1 · 2014 [cited by applicant]
WO WO2014140317A2 · 2014 [cited by applicant]
WO WO2014145090A1 · 2014 [cited by applicant]
WO WO2014177042A1 · 2014 [cited by applicant]
WO WO2014197854A1 · 2014 [cited by applicant]
WO WO2015038426A1 · 2015 [cited by applicant]
WO WO2015057699A2 · 2015 [cited by applicant]
WO WO2015069587A2 · 2015 [cited by applicant]
WO WO2015107425A2 · 2015 [cited by applicant]
WO WO2022147249A1 · 2022 [cited by applicant]
WO WO2022173976A1 · 2022 [cited by applicant]
WO WO2023064530A1 · 2023 [cited by applicant]
WO WO2023215481A1 · 2023 [cited by applicant]
WO WO2025007063A1 · 2025 [cited by applicant]
Beverborg NG, et al. (2021) Nature Communications. 12(5180):1-15. (https://doi.org/10.1038/s41467-021-25439-0). [cited by examiner]
Allen EHA, et al. (Jan. 2013) IOVS. 54(1):494-502. [cited by examiner]
Hammond SM, et al. (Jul. 29, 2021) bioRxiv. 26 pages. (doi: https://doi.org/10.1101/2021.07.29.454272). [cited by examiner]
Ito M, et al. (2005) FEBS Letters. 579:5988-5995. (doi:10.1016/j.febslet.2005.08.015). [cited by examiner]
Haraszti RA, et al. (2017) Nucleic Acids Research. 45(13):7581-7592. (doi: 10.1093/nar/gkx507). [cited by examiner]
Avilidty(R) Biosciences (Nov. 4, 2021) “Avidity Announces First Person Dosed with an Antibody Oligonucleotide Conjugate (AOC™)”. 3 pages. [cited by examiner]
McTiernan CF, et al. (1999) J Mol Cell Cardiol. 31:679-692. Article No. jmcc. 1998.0904. [cited by examiner]
Abramova, T. et al., Novel oligonucleotide analogues based on morpholino nucleoside subunits antisense technologies: New chemical possibilities. Indian Journal of Chemistry 48B:1721-1726 (2009). [cited by applicant]
Agarwal, Paresh et al. A Pictet-Spengler Ligation for Protein Chemical Modification. PNAS USA 110(1):46-51 (2013). [cited by applicant]
Albarran, Brian et al. Efficient intracellular delivery of a pro-apoptotic peptide with a pH-responsive carrier. Reactive and Functional Polymers 71(3):261-265 (2011). [cited by applicant]
Alegre, Maria-Luisa et al. Effect of a Single Amino Acid Mutation on the Activating and Immunosuppressive Properties of a “Humanized” OKT3 Monoclonal Antibody. Journal of Immunology 148(11):3461-3468 (1992). [cited by applicant]
Armanious, G.P. et al. GenBank Accession No. NM_002667. Version No. NM_002667.5. [cited by applicant]
Axup, Jun Y. et al. Synthesis of Site-specific Antibody-drug Conjugates Using Unnatural Amino Acids. PNAS USA 109(40):16101-16106 (2012). [cited by applicant]
Beigelman, Leonid et al. Chemical Modification of Hammerhead Ribozymes: Catalytic Activity and Nuclease Resistance. Journal of Biological Chemistry 270(43):25702-25708 (1995). [cited by applicant]
Biermans, Sam. Recombinant Adeno-Associated Virus as a Therapeutic Therapy for PLN R14del Patients. PLN Heart foundation Thesis. Retrieved from Retrieved from the internet: URL: https://plnheart.org/wp-content/uploads/R… [cited by applicant]
Bird, Robert E. et al. Single-chain Antigen-binding Proteins. Science 242(4877):423-426 (1988). [cited by applicant]
Blaney, Paul et al. Traceless Solid-phase Organic Synthesis. Chemical Reviews 102(7):2607-2624 (2002). [cited by applicant]
Bolger, Anthony M. et al. Trimmomatic: A Flexible Trimmer For Illumina Sequence Data. Bioinformatics 30(15):2114-2120 (2014). [cited by applicant]
Burlina, Fabienne et al. Chemical Engineering of RNase Resistant and Catalytically Active Hammerhead Ribozymes. Bioorganic and Medicinal Chemistry 5(11):1999-2010 (1997). [cited by applicant]
Casi, Giulio et al. Site-specific Traceless Coupling of Potent Cytotoxic Drugs to Recombinant Antibodies for Pharmacodelivery. Journal of the American Chemical Society 134(13):5887-5892 (2012). [cited by applicant]
Chen, Caifu et al. Real-Time Quantification Of microRNAs By Stem-loop RT-PCR. Nucleic Acids Research 33(20):e179, 1-9 (2005). [cited by applicant]
Clackson, Tim et al. Making Antibody Fragments using Phage Display Libraries. Nature 352(6336):624-628 (1991). [cited by applicant]
Colbere-Garapin, Florence et al. A New Dominant Hybrid Selective Marker for Higher Eukaryotic Cells. Journal of Molecular Biology 150(1):1-14 (1981). [cited by applicant]
Cole, S.P.C. et al. The EBV-Hybridoma Technique and its Application to Human Lung Cancer. Monoclonal Antibodies and Cancer Therapy 27:77-96 (1985). [cited by applicant]
Crouse, Gray F. et al. Expression and Amplification of Engineered Mouse Dihydrofolate Reductase Minigenes. Molecular Cell Biology 3(2):257-266 (1983). [cited by applicant]
Dawson, Philip E. et al. Modulation of Reactivity in Native Chemical Ligation through the Use of Thiol Additives. Journal of American Chemical Society 119(19):4325-4329 (1997). [cited by applicant]
Dawson, Philip E. et al. Synthesis of Proteins by Native Chemical Ligation. Science 266(5186):776-779 (1994). [cited by applicant]
Dimasi, Nazzareno et al. Development of a Trispecific Antibody Designed to Simultaneously and Efficiently Target Three Different Antigens on Tumor Cells. Molecular Pharmaceutics 12(9):3490-3501 (2015). [cited by applicant]
Dobin, Alexander et al. STAR: Ultrafast Universal RNA-seq Aligner. Bioinformatics 29(1):15-21 (2013). [cited by applicant]
Earnshaw, David J. et al. Modified Oligoribonucleotides as Site-Specific Probes of RNA Structure and Function. Biopolymers (Nucleic Acid Sciences) 48(1):39-55 (1998). [cited by applicant]
Gaffin, Robert D. et al. Long-Term Rescue of a Familial Hypertrophic Cardiomyopathy Caused by a Mutation in the Thin Filament Protein, Tropomyosin, via Modulation of a Calcium Cycling Protein. Journal of Molecular and C… [cited by applicant]
GenBank Accession No. XM_005551677. Version No. XM_005551677.2. Predicted: Macaca fascicularis phospholamban (PLN), mRNA: pp. 1-2. Record created Jan. 25, 2016. Retrieved Jul. 8, 2024. Retrieved from: https://www.ncbi.n… [cited by applicant]
GenBank Accession No. XM_015448593. Version No. XM_015448593.1. Ppredicted: Macaca fascicularis centrosomal protein 85kDa-like (CEP85L), transcript variant X2, mRNA: pp. 1-3. Record created Jan. 25, 2016. Retrieved Jul.… [cited by applicant]
Goldspiel, Barry R. et al. Human Gene Therapy. Clinical Pharmacy 12(7):488-505 (1993). [cited by applicant]
Griffey, Richard H. et al. 2′-O-aminopropyl Ribonucleotides: A Zwitterionic Modification that Enhances the Exonuclease Resistance and Biological Activity of Antisense Oligonucleotides. Journal of Medicinal Chemistry 39(… [cited by applicant]
Hackeng, Tilman M. et al. Protein Synthesis by Native Chemical Ligation: Expanded Scope by Using Straightforward Methodology. PNAS USA 96(18):10068-10073 (1999). [cited by applicant]
Hanes, Jozef et al. In Vitro Selection and Evolution of Functional Proteins by Using Ribosome Display. PNAS USA 94(10):4937-4942 (1997). [cited by applicant]
Hejesen, Christian et al. A Traceless Aryl-triazene Linker for DNA-directed Chemistry. Organic and Biomolecular Chemistry 11(15):2493-2497 (2013). [cited by applicant]
Huse, William D. et al. Generation Of A Large Combinatorial Library Of The Immunoglobulin Repertoire In Phage Lambda. Science 246(4935):1275-1281 (1989). [cited by applicant]
Huston, James S. et al. Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-digoxin Single-chain Fv Analogue Produced in [cited by applicant]
Idusogie, Esohe E. et al. Engineered Antibodies with Increased Activity to Recruit Complement. Journal of Immunology 166(4):2571-2575 (2001). [cited by applicant]
Kaneko, Etsuji et al. Optimizing Therapeutic Antibody Function: Progress with Fc Domain Engineering. Bio Drugs 25(1):1-11 (2011). [cited by applicant]
Karakikes, Ioannis et al. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nature Communications 6:6955, 1-10 (2015). [cited by applicant]
Karpeisky, Alexander et al. Highly Efficient Synthesis of 2-O-amino Nucleosides and their Incorporation in Hammerhead Ribozymes. Tetrahedron Letters 39(10):1131-1134 (1998). [cited by applicant]
Klocke, B. et al. GenBank Accession No. NM_001141927. Version No. NM_001141927.1. Mus musculus phospholamban (Pln), transcript variant 1, mRNA: pp. 1-4. Record created Nov. 20, 2008. Retrieved Jul. 8, 2024. Retrieved fr… [cited by applicant]
Kohler, G. et al. Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity. Nature 256(5517):495-497 (1975). [cited by applicant]
Koizumi, M. ENA Oligonucleotides as Therapeutics. Current Opinion in Molecular Therapeutics 8(2):144-149 (2006). [cited by applicant]
Kozbor, Danuta et al. The Production of Monoclonal Antibodies From Human Lymphocytes. Immunology Today 4(3):72-79 (1983). [cited by applicant]
Kutmeier, G. et al. Assembly of Humanized Antibody Genes from Synthetic Oligonucleotides Using a Single-round PCR. Biotechniques 17(2):242-246 (1994). [cited by applicant]
Lazar, Greg A. et al. Engineered Antibody Fc Variants with Enhanced Effector Function. PNAS USA 103(11):4005-4010 (2006). [cited by applicant]
Li, Bo et al. RSEM: Accurate Transcript Quantification From RNA-seq Data With Or Without A Reference Genome. BMC Bioinformatics 12:323, 1-16 (2011). [cited by applicant]
Loakes, David. Survey and Summary: The applications of universal DNA base analogues. Nucleic Acids Research 29(12):2437-2447 (2001). [cited by applicant]
Lowy, Israel et al. Isolation of Transforming DNA: Cloning the Hamster aprt Gene. Cell 22(3):817-823 (1980). [cited by applicant]
Lyon, Robert P. et al. Self-Hydrolyzing Maleimides improve the Stability and Pharmacological Properties of Antibody-drug Conjugates. Nature Biotechnology 32(10):1059-1062 (2014). [cited by applicant]
Martinez, Javier et al. Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAi. Cell 110(5):563-574 (2002). [cited by applicant]
McEnaney, Patrick J. et al. Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease. ACS Chemical Biology 7(7):1139-1151 (2012). [cited by applicant]
Moore, Gregory L. et al. Engineered Fc Variant Antibodies with Enhanced Ability to Recruit Complement and Mediate Effector Functions. mAbs 2(2):181-189 (2010). [cited by applicant]
Morgan, Richard A. et al. Human Gene Therapy. Annual Review of Biochemistry 62:191-217 (1993). [cited by applicant]
Morrison, Sherie L. et al. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. PNAS USA 81(21):6851-6855 (1984). [cited by applicant]
Mulligan, R. C. et al. Selection for Animal Cells That Express the [cited by applicant]
Mulligan, Richard C. The Basic Science of Gene Therapy. Science 260(5110):926-932 (1993). [cited by applicant]
Naisbitt, D. J et al. Disposition of Amodiaquine and Related Antimalarial Agents in Human Neutrophils: Implications for Drug Design. The Journal of Pharmacology and Experimental Therapeutics 280(2):884-893 (1997). [cited by applicant]
Natsume, Akito et al. Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities. Cancer Research 68(10):3863-3872 (2008). [cited by applicant]
Neuberger, Michael S. et al. Recombinant Antibodies Possessing Novel Effector Functions. Nature 312(5995):604-608 (1984). [cited by applicant]
Obika, Satosh et al. Synthesis of 2′-0,4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3′-endo sugar puckering. Tetrahedron Letters 38(50):8735-8738 (1997). [cited by applicant]
O'Hare, K. et al. Transformation of Mouse Fibroblasts to Methotrexate Resistance by a Recombinant Plasmid Expressing a Prokaryotic Dihydrofolate Reductase. PNAS USA 78(3):1527-1531 (1981). [cited by applicant]
PCT/US2024/036259 International Search Report and Written Opinion dated Dec. 3, 2024. [cited by applicant]
Perrault, Jean-Pierre et al. Mixed Deoxyribo- and Ribo-Oligonucleotides with Catalytic Activity. Nature 344(6266):565-568 (1990). [cited by applicant]
Pieken, Wolfgang A. et al. Kinetic Characterization of Ribonuclease-Resistant 2′-Modified Hammerhead Ribozymes. Science 253(5017):314-317 (1991). [cited by applicant]
Prabhakar, Rethinasamy et al. A Familial Hypertrophic Cardiomyopathy Alpha-tropomyosin Mutation Causes Severe Cardiac Hypertrophy And Death In Mice. Journal of Molecular and Cellular Cardiology 33(10):1815-1828 (2001). [cited by applicant]
Prabhakar, Rethinasamy et al. A Mouse Model Of Familial Hypertrophic Cardiomyopathy Caused By A Alpha-Tropomyosin Mutation. Molecular and Cellular Biochemistry 251(1-2):33-42 (2003). [cited by applicant]
Santerre, Robert F. et al. Expression of Prokaryotic Genes for Hygromycin B and G418 Resistance as Dominant-selection Markers in Mouse L Cells. Gene 30(1-3):147-156 (1984). [cited by applicant]
Schwarz, Dianne S. et al. Evidence that siRNAs Function as Guides, not Primers, in the [cited by applicant]
Shao, Yu et al. Rational design and rapid screening of antisense oligonucleotides for prokaryotic gene modulation. Nucleic Acids Research 34(19):5660-5669 (2006). [cited by applicant]
Shields, Robert L. et al. High Resolution Mapping of the Binding Site on Human IgG1 for Fc Gamma RI, Fc Gamma RII, Fc Gamma RIII, and FcRn and design of IgG1 Variants with Improved Binding to the Fc Gamma R. Journal of … [cited by applicant]
Skerra, Arne et al. Assembly of a Functional Immunoglobulin Fv Fragment in [cited by applicant]
Stavenhagen, Jeffrey B. et al. Enhancing the Potency of Therapeutic Monoclonal Antibodies via Fc Optimization. Advances in Enzyme Regulation 48(1):152-164 (2008). [cited by applicant]
Stavenhagen, Jeffrey B. et al. Fc Optimization of Therapeutic Antibodies Enhances their Ability to Kill Tumor Cells In vitro and Controls Tumor Expansion In vivo via Low-Affinity Activating Fcgamma Receptors. Cancer Res… [cited by applicant]
Strop, Pavel et al. Location Matters: Site of Conjugation Modulates Stability and Pharmacokinetics of Antibody Drug Conjugates. Chemistry and Biology 20(2):161-167 (2013). [cited by applicant]
Summerton, James E., Morpholino, siRNA, and S-DNA Compared: Impact of Structure and Mechanism of Action on Off-Target Effects and Sequence Specificity. Current Topics in Medicinal Chemistry 7:651-660 (2007). [cited by applicant]
Szybalska, Elizabeth Hunter et al. Genetics of Human Cell Lines, IV. DNA-mediated Heritable Transformation of a Biochemical Trait. PNAS USA 48(12):2026-2034 (1962). [cited by applicant]
Takeda, Shun-Ichi et al. Construction of Chimaeric Processed Immunoglobulin Genes Containing Mouse Variable and Human Constant Region Sequences. Nature 314(6010):452-454 (1985). [cited by applicant]
Tolstoshev, Paul. Gene Therapy, Concepts, Current Trials and Future Directions. Annual Review Pharmacology and Toxicology 32:573-596 (1993). [cited by applicant]
US Food and Drug Administration. Guide for the Care and Use of Laboratory Animals. US National Institutes of Health:1-246 (2011). [cited by applicant]
U.S. Appl. No. 18/759,724 Office Action dated Mar. 3, 2025. [cited by applicant]
Usman, Nassim et al. Exploiting the Chemical Synthesis of RNA. Trends in Biochemical Sciences 17:334-339 (1992). [cited by applicant]
Verma, Sandeep et al. Modified Oligonucleotides: Synthesis and Strategy for Users. Annual Review of Biochemistry 67(1):99-134 (1998). [cited by applicant]
Ward, E Sally et al. Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted from [cited by applicant]
Wigler, M. et al. Transformation of Mammalian Cells With an Amplifiable Dominant-acting Gene. PNAS USA 77(6):3567-3570 (1980). [cited by applicant]
Wigler, Michael et al. Transfer of Purified Herpes Virus Thymidine Kinase Gene to Cultured Mouse Cells. Cell 11(1):223-232 (1977). [cited by applicant]
Wu, Bin et al. Building Complex Glycopeptides: Development of a Cysteine-free Native Chemical Ligation Protocol. Angewandte Chemie 45(25):4116-4125 (2006). [cited by applicant]
Wu, George Y. et al. Delivery systems for Gene Therapy. Biotherapy 3(1):87-95 (1991). [cited by applicant]
Wu, Peng et al. Site-specific Chemical Modification of Recombinant Proteins Produced in Mammalian Cells by Using the Genetically Encoded Aldehyde Tag. PNAS USA 106(9):3000-3005 (2009). [cited by applicant]
Yoshida, Tokuyuki et al. Evaluation of off-target effects of gapmer antisense oligonucleotides using human cells. Genes to Cells 24(12):827-835 (2019). [cited by applicant]
Zhang, Andrew X. et al. A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules. Journal of the American Chemical Society 132(36):12711-12716 (2010). [cited by applicant]