IP Library › Granted Patent US 12,545,929
Granted Patent B2
US 12,545,929 · App. 17/741,666 · Granted Feb 10, 2026

Lactam-modified adeno-associated virus vectors

Inventors: Willem Broekaert (Dilbeek, BE); Melanie Glossop (Canterbury, GB); Karl Gibson (Canterbury, GB); Nicolas Ferry (Boulogne Billancourt, FR); Gaëlle Lefèvre (Bourg-la-Reine, FR)
Assignee: Coave Therapeutics
C12N15/86C07D205/08A61K48/00C12N2750/14121C12N2750/14122C12N2750/14143C12N2750/14151
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Quick Facts
Patent No.
US 12,545,929
App. No.
17/741,666
Granted
Feb 10, 2026
Kind
B2
Abstract

The present invention relates to adeno-associated virus (AAV) vectors modified by the covalent coupling of at least one compound comprising a lactam moiety (e.g., β-lactam) to at least one amino group of an amino acid residue of the capsid of the AAV vectors. The AAV vectors are useful in transducing a cell, especially for gene therapy.

Claims (42)

1 . An adeno-associated virus (AAV) vector comprising a moiety according to formula (II):

or a pharmaceutically acceptable salt thereof, wherein

N* is a nitrogen atom of an amino group of an amino acid residue of the AAV vector's capsid;

----- represents the point of attachment to the AAV vector's capsid;

Z is a functional moiety comprising a cell-type specific ligand, a labelling agent, a steric shielding agent, a drug moiety or combinations thereof;

L is a linker;

R 1 , R 1 , R 2 and R 2′ are each independently hydrogen, halogen, or an optionally substituted C 1-6 alkyl; or

R 1 and R 1′ or R 2 and R 2′ , together with their intervening atoms, may come together of form an optionally substituted spiro-fused ring; or

R 1 and R 2 , together with their intervening atoms, may form an optionally substituted 3- to 7-membered saturated, partially unsaturated, or aryl or heteroaryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2 . The AAV vector according to claim 1 , wherein at least one N* is a nitrogen atom of an amino group of a lysine residue of the AAV vector's capsid.

3 . The AAV vector according to claim 1 , wherein Z comprises or consists of a cell-type specific ligand selected from the group consisting of saccharides, hormones, peptides, proteins or functionally active fragments thereof, membrane receptors or functionally active fragments thereof, antibodies or functionally active fragments thereof, spiegelmers, nucleic acid or peptide aptamers, vitamins, and drugs.

4 . The AAV vector according to claim 3 , wherein Z is selected from the group consisting of mannose, galactose, fucose, desosamine, N-acetylglucosamine, N-acetylgalactosamine, S6-galactose, S6-N-acetylgalactosamine, glucuronic acid, P6-galactose and P1-galactose.

5 . The AAV vector according to claim 1 , wherein Z comprises or consists of a steric shielding agent selected from the group consisting of polyethylene glycol, pHPMA, and polysaccharides.

6 . The AAV vector according to claim 1 , wherein L comprises an optionally substituted group comprising saturated or unsaturated, linear or branched C 2 -C 40 hydrocarbon chains, polyethylene glycol, polypropylene glycol, pHPMA, PLGA, polymers of alkylene diamines, and combinations thereof.

7 . The AAV vector according to claim 6 , wherein L comprises a polyethylene glycol (PEG), comprising 2 to 40 ethylene glycol monomers.

8 . The AAV vector according to claim 1 , comprising a moiety according to formula (IIa)

or a pharmaceutically acceptable salt thereof, wherein

L 1 is an optionally substituted aryl or heteroaryl group;

L 2 is an optionally substituted heteroaryl group; and

L 3 is a linker.

9 . The AAV vector according to claim 1 , comprising a moiety according to formula (IIc):

or a pharmaceutically acceptable salt thereof, wherein

L 3 is a linker;

R 3 , R 3′ , R 4 and R 4′ are each independently hydrogen, halogen, —OR, —NR 2 , —CN, —SR or an optionally substituted group selected from C 1-6 alkyl or a 3- to 7-membered saturated, partially unsaturated, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected form nitrogen, oxygen, or sulfur; or

R 3 and R 4 , or R 3′ and R 4′ , together with their intervening atoms, may form an optionally substituted 3- to 7-membered saturated, partially unsaturated, aryl or heteroaryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently selected from hydrogen or C 1-6 alkyl; and

each **** is independently a single or double bond.

10 . The AAV vector according to claim 9 , wherein L 3 is an optionally substituted group selected from the group consisting of saturated or unsaturated, linear or branched C 2 -C 40 hydrocarbon chains, polyethylene glycol, polypropylene glycol, pHPMA, PLGA, polymers of alkyl diamines and combinations thereof; preferably L 3 is polyethylene glycol.

11 . The AAV vector according to claim 1 , comprising a moiety according to formula (IIe)

or a pharmaceutically acceptable salt thereof, wherein

R 3 , R 3′ , R 4 and R 4′ are each independently hydrogen, halogen, —OR, —NR 2 , —CN, —SR or an optionally substituted group selected from C 1-6 alkyl or a 3- to 7-membered saturated, partially unsaturated, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

R 3 and R 4 , or R 3′ and R 4′ , together with their intervening atoms, may form an optionally substituted 3- to 7-membered saturated, partially unsaturated, aryl or heteroaryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently selected from hydrogen or C 1-6 alkyl; and

n is an integer ranging from 1 to 20.

12 . The AAV vector according to claim 1 , comprising:

or a pharmaceutically acceptable salt thereof.

13 . The AAV vector according to claim 1 , wherein said AAV vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, pseudotypes, chimeras, and variants thereof.

14 . The AAV vector according to claim 1 , wherein said AAV vector comprises at least one transgene, and wherein the transgene is optionally under control of a promoter.

15 . The AAV vector according to claim 14 , wherein said AAV vector comprises at least one transgene comprising the cDNA from a GBA gene.

16 . A pharmaceutical composition comprising an AAV vector according to claim 1 and at least one pharmaceutically acceptable vehicle.

17 . The AAV vector according to claim 1 , wherein R 1 , R 1′ , R 2 and R 2′ are hydrogen.

18 . The AAV vector according to claim 8 , wherein L 2 is an optionally substituted 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 28, 2022
From: BROEKAERT, WILLEM; GLOSSOP, MELANIE; GIBSON, KARL; FERRY, NICOLAS; LEFEVRE, GAELLE
To: COAVE THERAPEUTICS
Reel/Frame 061241/0639 →
Continuity (2)
Provisional Application 63187648 · May 12, 2021
Related Publication 20220380803A1 · Dec 1, 2022
References Cited (97)
US 6335324B1 · Bisacchi et al. · 2002 [cited by applicant]
US 10087217B2 · Zhou et al. · 2018 [cited by applicant]
US 11382988B2 · Moullier et al. · 2022 [cited by applicant]
US 20040147502A1 · Bisacchi et al. · 2004 [cited by applicant]
US 20040180855A1 · Schumacher et al. · 2004 [cited by applicant]
US 20100098666A1 · Wright · 2010 [cited by applicant]
US 20140336245A1 · Mingozzi et al. · 2014 [cited by applicant]
US 20150017703A1 · Agnew · 2015 [cited by applicant]
US 20160297855A1 · Zhou et al. · 2016 [cited by applicant]
US 20170128594A1 · Wright · 2017 [cited by applicant]
US 20180201907A1 · Agnew · 2018 [cited by applicant]
US 20180371496A1 · Li et al. · 2018 [cited by applicant]
US 20190203227A1 · Ho et al. · 2019 [cited by applicant]
US 20190388557A1 · Mevel et al. · 2019 [cited by applicant]
US 20200157570A1 · Loiler · 2020 [cited by applicant]
US 20200172913A1 · Desai et al. · 2020 [cited by applicant]
US 20200224219A1 · Buning et al. · 2020 [cited by applicant]
US 20200325456A1 · Li et al. · 2020 [cited by applicant]
US 20200340012A1 · Mali et al. · 2020 [cited by applicant]
US 20200405639A1 · Zhang et al. · 2020 [cited by applicant]
US 20210162072A1 · Moullier et al. · 2021 [cited by applicant]
US 20220323610A1 · Moullier et al. · 2022 [cited by applicant]
WO WO199967215A1 · 1999 [cited by applicant]
WO WO2005106046A1 · 2005 [cited by applicant]
WO WO2008128251A1 · 2008 [cited by applicant]
WO WO2011082285A1 · 2011 [cited by applicant]
WO WO2013078400A1 · 2013 [cited by applicant]
WO WO2013112778A1 · 2013 [cited by applicant]
WO WO2015048534A1 · 2015 [cited by applicant]
WO WO2017053629A2 · 2017 [cited by applicant]
WO WO2017212019A1 · 2017 [cited by applicant]
WO WO2018035503A1 · 2018 [cited by applicant]
WO WO2018191750A2 · 2018 [cited by applicant]
WO WO2018226602A1 · 2018 [cited by applicant]
WO WO2019032917A1 · 2019 [cited by applicant]
WO WO2019063747A1 · 2019 [cited by applicant]
WO WO2019126356A1 · 2019 [cited by applicant]
WO WO2021005210A1 · 2021 [cited by applicant]
WO WO2022096681A1 · 2022 [cited by applicant]
Nicolson et al., “Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High-Throughput Screens”, J. Virology, vol. 90, No. 16, 7019-7031 (2016) (Year: 2… [cited by examiner]
Mehta et al., “2-Azetindinone—A New Profile of Various Pharmacological Activities”, Eu. J. of Med. Chem., vol. 45. Issue 12, pp. 551-5560 (Dec. 2010)); (Year: 2010). [cited by examiner]
Beutler , “AAV Provides an Alternative for Gene Therapy of the Peripheral Sensory (or Central) Nervous System”, Mol Ther. Apr. 2010; 18(4): 670-673. (Year: 2010). [cited by examiner]
Thadani et al. ACS Synth Biol (2020) 9(3):461-467 (Year: 2020). [cited by examiner]
Pham et al Nanoscale 2024 16(29):13820-13833 (Year: 2024). [cited by examiner]
Albright, B. H. et al., Mapping the structural determinants required for AAVrh.10 Transport across the BBB, Mol. Ther., 26(2):510-523 (2018). [cited by applicant]
Asano, S. et al., Preparation and Activities of Macromolecule Conjugates of the CCR5 Antagonist Maraviroc, ACS Med. Chem. Lett., 5:133-137 (2014). [cited by applicant]
Aschauer, D. F. et al., Analysis of Transduction Efficiency, Tropism and Axonal Transport of AAV Serotypes 1, 2, 5, 6, 8 and 9 in the Mouse Brain, PLoS One. 8(9):e76310 (2013). [cited by applicant]
Asokan, A. et al., Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle, Nat. Biotechnol., 28(1):79-82 (2010). [cited by applicant]
Bartel, M. A. et al., Directed evolution of novel adeno-associated viruses for therapeutic gene delivery, Gene Ther., 19(6):694-700 (2012). [cited by applicant]
Bevan, A. K. et al., Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders, Mol Ther., 19(11):1971-80 (2011). [cited by applicant]
Boutin, S. et al., Prevalence of Serum IgG and Neutralizing Factors Against Adeno-Associated Virus AAV Types 1, 2, 5, 6, 8, and 9 in the healthy population, Implications for Gene Therapy Using AAV Vectors, Hum. Gene The… [cited by applicant]
Burger, C. et al., Recombinant AAV Viral Vectors Pseudotyped with Viral Cpasids from Serotypes 1, 2, and 5 Display Differential Efficiency and Cell Tropism after Delivery to Different Regions of the Central Nervous Syst… [cited by applicant]
Cearley, C. N. and Wolfe, J. H., Transduction Characteristics of Adeno-associated Virus Vectors Expressing Cap Serotypes 7, 8, 9, and Rh10 in the Mouse Brain, Mol. Ther., 13(3):528-37 (2006). [cited by applicant]
Cearley, C. N. et al., Expanded Repertoire of AAV Vector Serotypes Mediate Unique Patterns of Transduction in Mouse Brain, Mol. Ther., 16(10):1710-8 (2008). [cited by applicant]
Ellinwood, M. N. et al., Safe, Efficient, and Reproducible Gene Therapy of the Brain in the Dog Models of Sanfilippo and Hurler Syndromes, Mol. Ther., 19(2):251-259 (2011). [cited by applicant]
Foust, K. D. et al., Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes, Nat. Biotechnol., 27(1):59-65 (2009). [cited by applicant]
Fu, H. et al., Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III, Perspective for AAV-Mediated Gene Therapy, Hum. Gene Ther. Clin. Dev.,… [cited by applicant]
Girod, A. et al., Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat. Med., 5(9):1052-1056 (1999). [cited by applicant]
Gray, S. J. et al., Directed Evolution of a Novel Adeno-associated Virus AAV Vector That Crosses the Seizure-compromised Blood-Brain Barrier BBB, Mol. Ther., 18(3):570-8 (2010). [cited by applicant]
Gray, S. J. et al., Global CNS Gene Delivery and Evasion of Anti-AAV Neutralizing Antibodies by Intrathecal AAV Administration in Non-Human Primates, Gene Ther. 20(4):450-9 (2013). [cited by applicant]
Gray, S. J. et al., Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia, A comparative Study of Adult Mice and Nonhuman Primates, Mol. Ther., 19(6):1058-69 (2011). [cited by applicant]
Hinderer, C. et al., Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals, Hum. Gene Thera., 29(1):15-24 (2018). [cited by applicant]
Hocquemiller, M. et al., Adeno—Associated Virus-Based Gene Therapy for CNS Diseases, Human Gene Therapy, 27(7):478-496 (2016). [cited by applicant]
Hordeaux, J. et al., The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice, Mol. Ther., 26(3):664-668 (2018). [cited by applicant]
Hudry, E. et al., Exosome-associated AAV vector as a robust and convenient neuroscience tool, Gene Ther., 23:380-92 (2016). [cited by applicant]
International Search Report for PCT/EP2021/080832, 9 pages (mailed Feb. 21, 2022). [cited by applicant]
Katrekar, D. et al., Oligonucleotide conjugated multifunctional adeno-associated viruses, Sci. Rep., 8(3589):1-8 (2018). [cited by applicant]
Koerber, J. T. et al., Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles, Nat. Protoc., 1(2):701-6 (2006). [cited by applicant]
Kwon, I. and Schaffer, D., Designer Gene Delivery Vectors, Molecular Engineering and Evolution of Adeno-Associated Viral Vectors for Enhanced Gene Transfer, Pharm. Res., 25(3):489-99 (2008). [cited by applicant]
Kye-Il, J. et al., Enhanced Real-Time Monitoring of Adena-Associated Virus Trafficking by Virus-Quantum Dot Conjugates, ACS Nano, 5(5):3523-3535 (2011). [cited by applicant]
Lee, G. K. et al., PEG Conjugation Moderately Protects Adeno-Associated Viral Vectors Against Antibody Neutralization, Biotechnol. Bioeng., 92:24-34 (2005). [cited by applicant]
Liguore, W. A. et al., AAV-PHP.B Administration Results in a Differential Pattern of CNS Biodistribution in Non-human Primates Compared with Mice, Mol. Thera., 27(11):2018-2037 (2019). [cited by applicant]
Lykken, E. A. et al., Recent progress and considerations for AAV gene therapies targeting the central nervous system, J. Neurodev. Disord., 10(1):16 (2018). [cited by applicant]
Maguire, C. A. et al., Microvesicle-associated AAV Vector as a Novel Gene Delivery System, Mol. Ther., 20:960-71 (2012). [cited by applicant]
Maheshri, N. et al., Directed evolution of adeno-associated virus yields enhanced gene delivery vectors, Nat. Biotechnol., 24(2):198-204 (2006). [cited by applicant]
Marsic, D. and Zolotukhin, S., Altering Tropism of rAAV by Directed Evolution, Methods Mole. Biol., 1382:151-173 (2016). [cited by applicant]
Mccurdy, V. J. et al., Sustained normalization of neurological disease after intracranial gene therapy in a feline model, Sci. Transl. Med., 6(231):1-24 (2014). [cited by applicant]
Mcphee, S. W. J. et al., Immune responses to AAV in a phase I study for Canavan disease, J. Gene Med., 8:577-588 (2006). [cited by applicant]
Mével, M. et al., Chemical modification of the adeno-associated virus capsid to improve gene delivery, Chem. Sci., 11:1122-1131 (2020). [cited by applicant]
Mevel, M. et al., Chemical modification of the adeno-associated virus capsid to improve gene delivery, Chem. Sci., 10 pages (2019). [cited by applicant]
Miyake, N. et al., Global gene transfer into the CNS across the BBB after neonatal systemic delivery of single-stranded AAV vectors, Brain Res., 1389:19-26 (2011). [cited by applicant]
Niethammer, M. et al., Long-term follow-up of randomized AAV2-GAD gene therapy trial for Parkinson's diease, JCI Insight, 2(7):e90133 (2017). [cited by applicant]
Perabo, L. et al., Artificial Evolution with Adeno-Associated Viral Libraries, Comb. Chem. High Throu. Screen., 11:118-126 (2008). [cited by applicant]
Rabinowitz, J. E. et al., Insertional Mutagenesis of AAV2 Capsid and the Production of Recombinant Virus, Virology, 265(2):274-85 (1999). [cited by applicant]
Raja, K. S. et al., Icosahedral Virus Particles as Polyvalent Carbohydrate Display Platforms, ChemBioChem, 4:1348-1351 (2003). [cited by applicant]
Samaranch, L. et al., AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate CNS Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction, Mol. Ther., 22(2):329-37 (2014). [cited by applicant]
Samaranch, L. et al., Adeno-Associated Virus Serotype 9 Transduction in the CNS of Nonhuman Primates, Hum. Gene Ther., 23(4):382-9 (2012). [cited by applicant]
Sato, S. et al., Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors, ACS Med. Chem. Lett., 4:460-465 (2013). [cited by applicant]
Schaffer, D. V. and Maheshri, N., Directed Evolution of AAV Mutants for Enhanced Gene Delivery, 26th Annual International Conference of the IEEE EMBS, San Francisco, CA, 3520-3523 (Sep. 2004). [cited by applicant]
Shen, S. et al., Engraftment of a Galactose Receptor Footprint onto Adeno-associated Viral Capsids Improves Transduction Efficiency, J. Biol. Chem., 288(40):28814-23 (2013). [cited by applicant]
Sletten, E. M. and Bertozzi, C. R., Bioorthogonal chemistry: fishing for selectivity in a sea of functionalit, Angew. Chem. Int. Ed. Engl., 48(38):6974-98 (2009). [cited by applicant]
Taymans, J-M. et al., Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain, Hum. Gene Ther., 18(3):195-206 (2007). [cited by applicant]
Tse, L. V. et al., Structure-guided evolution of antigenically distinct AAV variants for immune evasion, Proc. Natl. Acad. Sci. USA, 114(24):E4812-E4821 (2017). [cited by applicant]
Vite, C. H. et al., Effective Gene Therapy for an Inherited CNS Disease in a Large Animal Model, Annals Neuro., 57(3):355-364 (2005). [cited by applicant]
Watakabe, A. et al., Comparative analyses of AAV vector serotypes 1, 2, 5, 8 and 9 in marmoset, mouse and macaque cerebral cortex, Neurosci. Res., 93:144-57 (2015). [cited by applicant]
Wobus, C. E. et al., Monoclonal Antibodies against the Adena-Associated Virus Type 2 (AAV-2) Capsid: Epitope Mapping and Identification of Capsid Domains Involved in AAV-2-Cell Interaction and Neutralization of AAV-2 In… [cited by applicant]
Zuleta, A. et al., AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington's disease, Biochem. Biophys. Res. Comm., 420(3):558-563 (… [cited by applicant]