Granted Patent
B2
US 12,258,597 · App. 16/968,452 · Granted Mar 25, 2025
Methods and compositions for therapeutic protein delivery
Inventors:
Andrew Baik (Scarsdale, NY); Katherine Cygnar (New York, NY); Maria Praggastis (Cortlandt Manor, NY)
Assignee:
Regeneron Pharmaceuticals, Inc.
C12N9/2408A61K48/005A61P3/00C07K16/2881C07K16/2896C12Y302/0102A61K2039/505C07K2317/622C07K2319/33C12N2750/14143
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Compositions and methods for delivering a therapeutic protein to the central nervous system (CNS), in order to treat diseases and disorders that impair the CNS, such as treating lysosomal storage diseases are disclosed. Therapeutic proteins delivered via a therapeutically effective amount of a nucleotide composition encoding the therapeutic protein conjugated to a cell surface receptor-binding protein that crosses the blood brain barrier (BBB) are provided.
Claims (26)
1. A multidomain therapeutic protein comprising a first delivery domain, a second delivery domain, and an enzyme domain, wherein the first delivery domain binds human transferrin receptor (hTfR), and wherein the second delivery domain comprises a single-chain variable fragment (scFv) that binds CD63, wherein the scFv that binds CD63 comprises the sequence set forth in SEQ ID NO: 2.
2. The multidomain therapeutic protein of claim 1 , wherein the first delivery domain comprises a single-chain variable fragment (scFv).
3. The multidomain therapeutic protein of claim 2 , wherein the first delivery domain scFv or the second delivery domain scFv is fused to an Fc.
4. The multidomain therapeutic protein of claim 3 , wherein the Fc comprises a wildtype human IgG4 isotype.
5. The multidomain therapeutic protein of claim 3 , wherein GAA is conjugated to the carboxy terminus of the Fc.
6. The multidomain therapeutic protein of claim 1 , wherein the first delivery domain comprises a half-body.
7. The multidomain therapeutic protein of claim 1 , wherein the enzyme domain is alpha-glucosidase (GAA).
8. The multidomain therapeutic protein of claim 1 , wherein the multidomain therapeutic protein comprises the sequence set forth in SEQ ID NO: 10.
9. The multidomain therapeutic protein of claim 8 , comprising an anti-hTfR scFv and an anti-hCD63 scFv, wherein the anti-hTfR scFv and anti-hCD63 scFv are both linked, at their carboxy termini, to a single GAA enzyme.
10. The multidomain therapeutic protein of claim 1 , wherein the first delivery domain is an anti-hTfR scFv, and the enzyme domain is linked to carboxy terminus of the VL domain of the anti-hTfR scFv.
11. The multidomain therapeutic protein of claim 10 , wherein the second delivery domain is linked to the N-terminus of the VH domain of the anti-hTfR scFv.
12. The multidomain therapeutic protein of claim 1 , wherein the enzyme domain comprises the amino acid sequence set forth in SEQ ID NO: 1.
13. A polynucleotide encoding the multidomain therapeutic protein of claim 1 .
14. The polynucleotide of claim 13 , further comprising a virus nucleic acid sequence.
15. The polynucleotide of claim 14 , wherein the virus nucleic acid sequence is an adeno-associated virus (AAV) nucleic acid sequence.
16. The polynucleotide of claim 13 , further comprising a virus nucleic acid sequence and a locus-targeting nucleic acid sequence, wherein the virus nucleic acid sequence is an adeno-associated virus (AAV) nucleic acid sequence.
17. The polynucleotide of claim 13 , further comprising a tissue specific regulatory element that is a liver specific promoter or a neuronal specific promoter.
18. The polynucleotide of claim 17 , wherein the tissue specific regulatory element comprises the sequence set forth in SEQ ID NO:8 and/or SEQ ID NO:9.
19. A gene therapy vector comprising a polynucleotide of claim 13 .
20. The gene therapy vector of claim 19 , wherein the gene therapy vector is selected from the group consisting of:
a viral vector;
a naked polynucleotide; and
a polynucleotide complex that is a lipid nanoparticle comprising the polynucleotide and lipids.
21. The gene therapy vector of claim 20 , wherein the gene therapy vector is an AAV9, an Anc80, an AAV2/8 chimera, or an AAV pseudotyped to the liver or neuronal tissue.
22. The gene therapy vector of claim 19 , wherein the gene therapy vector is a viral vector selected from the group consisting of a retrovirus, an adenovirus, a herpes simplex virus, a pox virus, a vaccinia virus, a lentivirus, and an adeno-associated virus.
23. A method of delivering a therapeutic protein to the central nervous system (CNS) of a patient, comprising delivering the polynucleotide of claim 13 encoding the multidomain therapeutic protein to the liver of the patient to form a liver depot for the production and secretion of the multidomain therapeutic at a consistent serum level of at least 1 g/mL over consecutive days, weeks or months following delivery to provide a therapeutically effective amount of the multidomain therapeutic protein in the CNS.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 14, 2022
From: BAIK, ANDREW; CYGNAR, KATHERINE; PRAGGASTIS, MARIA
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 059006/0430 →
Continuity (3)
Provisional Application
62777683
· Dec 10, 2018
Provisional Application
62627721
· Feb 7, 2018
References Cited (400)
US 4444878A
· Paulus
· 1984
[cited by applicant]
US 5030717A
· Tramontano et al.
· 1991
[cited by applicant]
US 5126258A
· Lerner et al.
· 1992
[cited by applicant]
US 5156965A
· Schochetman et al.
· 1992
[cited by applicant]
US 5229272A
· Paul et al.
· 1993
[cited by applicant]
US 5436153A
· Sprecher et al.
· 1995
[cited by applicant]
US 5441931A
· Sprecher et al.
· 1995
[cited by applicant]
US 5585108A
· Ruddy et al.
· 1996
[cited by applicant]
US 5602021A
· Davis et al.
· 1997
[cited by applicant]
US 5677146A
· Sprecher et al.
· 1997
[cited by applicant]
US 5731168A
· Carter et al.
· 1998
[cited by applicant]
US 5858351A
· Podsakoff et al.
· 1999
[cited by applicant]
US 5935854A
· Sprecher et al.
· 1999
[cited by applicant]
US 5962313A
· Podsakoff et al.
· 1999
[cited by applicant]
US 6265389B1
· Burke
· 2001
[cited by applicant]
US 6335011B1
· Podsakoff et al.
· 2002
[cited by applicant]
US 6372205B1
· Duncan et al.
· 2002
[cited by applicant]
US 6387674B1
· Trasciatti et al.
· 2002
[cited by applicant]
US 6479265B1
· Napper et al.
· 2002
[cited by applicant]
US 6555525B2
· Burke
· 2003
[cited by applicant]
US 6610290B2
· Podsakoff et al.
· 2003
[cited by applicant]
US 6703488B1
· Burton et al.
· 2004
[cited by applicant]
US 6855804B2
· Paul et al.
· 2005
[cited by applicant]
US 7041298B2
· Deshaies et al.
· 2006
[cited by applicant]
US 7105348B2
· Murphy et al.
· 2006
[cited by applicant]
US 7223556B1
· Zhou et al.
· 2007
[cited by applicant]
US 7335504B2
· Haupts et al.
· 2008
[cited by applicant]
US 7371539B2
· Church et al.
· 2008
[cited by applicant]
US 7431923B2
· Young et al.
· 2008
[cited by applicant]
US 7442777B2
· Young et al.
· 2008
[cited by applicant]
US 7560424B2
· LeBowitz et al.
· 2009
[cited by applicant]
US 7704492B2
· Podsakoff et al.
· 2010
[cited by applicant]
US 7785856B2
· LeBowitz et al.
· 2010
[cited by applicant]
US 7858367B2
· Amalfitano et al.
· 2010
[cited by applicant]
US 8048991B2
· Lundgren-Åkerlund
· 2011
[cited by applicant]
US 8257745B2
· Ketelson et al.
· 2012
[cited by applicant]
US 8278036B2
· Kariko et al.
· 2012
[cited by applicant]
US 8563255B2
· Lundgren-Åkerlund
· 2013
[cited by applicant]
US 8618264B2
· Cunningham et al.
· 2013
[cited by applicant]
US 8642835B2
· Macdonald et al.
· 2014
[cited by applicant]
US 8679478B2
· Koeberl
· 2014
[cited by applicant]
US 8785168B2
· LeBowitz et al.
· 2014
[cited by applicant]
US 8883979B2
· Ma et al.
· 2014
[cited by applicant]
US 8974791B2
· Pardridge et al.
· 2015
[cited by applicant]
US 9023357B2
· Ma et al.
· 2015
[cited by applicant]
US 9186420B2
· Koeberl
· 2015
[cited by applicant]
US 9241989B2
· Otto et al.
· 2016
[cited by applicant]
US 9302015B2
· Papadopoulos et al.
· 2016
[cited by applicant]
US 9315790B2
· Sakuraba et al.
· 2016
[cited by applicant]
US 9353186B2
· Freiberg et al.
· 2016
[cited by applicant]
US 9453241B2
· Pan
· 2016
[cited by applicant]
US 9545450B2
· Do
· 2017
[cited by applicant]
US 9545451B2
· Papadopoulos et al.
· 2017
[cited by applicant]
US 9611323B2
· Dennis et al.
· 2017
[cited by applicant]
US 9622459B2
· Macdonald et al.
· 2017
[cited by applicant]
US 9629801B2
· Shusta et al.
· 2017
[cited by applicant]
US 9649374B2
· Otto et al.
· 2017
[cited by applicant]
US 9688764B2
· Papadopoulos et al.
· 2017
[cited by applicant]
US 9708406B2
· Zhang et al.
· 2017
[cited by applicant]
US 9738717B2
· Azorsa
· 2017
[cited by applicant]
US 9777063B2
· Freiberg et al.
· 2017
[cited by applicant]
US 9849195B2
· Davidson
· 2017
[cited by applicant]
US 9873868B2
· Koeberl et al.
· 2018
[cited by applicant]
US 20030219415A1
· Podsakoff et al.
· 2003
[cited by applicant]
US 20040204379A1
· Cheng et al.
· 2004
[cited by applicant]
US 20040248262A1
· Koeberl et al.
· 2004
[cited by applicant]
US 20040258666A1
· Passini et al.
· 2004
[cited by applicant]
US 20050142141A1
· Pardridge et al.
· 2005
[cited by applicant]
US 20050244400A1
· LeBowitz et al.
· 2005
[cited by applicant]
US 20060078542A1
· Mah et al.
· 2006
[cited by applicant]
US 20060099184A1
· Podsakoff et al.
· 2006
[cited by applicant]
US 20060171926A1
· Passini et al.
· 2006
[cited by applicant]
US 20060210474A1
· Young et al.
· 2006
[cited by applicant]
US 20080044408A1
· Young et al.
· 2008
[cited by applicant]
US 20080069803A1
· Podsakoff et al.
· 2008
[cited by applicant]
US 20080089891A1
· Hahn et al.
· 2008
[cited by applicant]
US 20080279945A1
· Mah et al.
· 2008
[cited by applicant]
US 20090117091A1
· LeBowitz et al.
· 2009
[cited by applicant]
US 20090155262A1
· Young et al.
· 2009
[cited by applicant]
US 20090191178A1
· Zankel et al.
· 2009
[cited by applicant]
US 20100221225A1
· Byrne et al.
· 2010
[cited by applicant]
US 20110223147A1
· Lebowitz et al.
· 2011
[cited by applicant]
US 20110223176A1
· Barlow et al.
· 2011
[cited by applicant]
US 20120093794A1
· LeBowitz et al.
· 2012
[cited by applicant]
US 20120183502A1
· Meeker et al.
· 2012
[cited by applicant]
US 20120283503A1
· Ostrovska et al.
· 2012
[cited by applicant]
US 20120315276A1
· Otto et al.
· 2012
[cited by applicant]
US 20120322861A1
· Byrne et al.
· 2012
[cited by applicant]
US 20130022606A1
· Otto et al.
· 2013
[cited by applicant]
US 20130171147A1
· Otto et al.
· 2013
[cited by applicant]
US 20130243775A1
· Papadopoulos et al.
· 2013
[cited by applicant]
US 20140079711A1
· Cunningham et al.
· 2014
[cited by applicant]
US 20140186326A1
· Canfield et al.
· 2014
[cited by applicant]
US 20150093393A1
· Ma et al.
· 2015
[cited by applicant]
US 20150196671A1
· Byrne et al.
· 2015
[cited by applicant]
US 20150252116A1
· Ma et al.
· 2015
[cited by applicant]
US 20150322149A1
· Bohrmann et al.
· 2015
[cited by applicant]
US 20160002342A1
· Ma et al.
· 2016
[cited by applicant]
US 20160089451A1
· Armstrong
· 2016
[cited by applicant]
US 20170008965A1
· Ma et al.
· 2017
[cited by applicant]
US 20170189497A1
· Do et al.
· 2017
[cited by applicant]
US 20170204191A1
· Bamdad
· 2017
[cited by examiner]
US 20170260292A1
· Dennis et al.
· 2017
[cited by applicant]
US 20180028676A1
· Armstrong
· 2018
[cited by applicant]
US 20180036388A1
· McIvor et al.
· 2018
[cited by applicant]
US 20180230212A1
· Hosen et al.
· 2018
[cited by applicant]
US 20180236105A1
· Davidson et al.
· 2018
[cited by applicant]
US 20180251571A1
· Armstrong et al.
· 2018
[cited by applicant]
US 20180264090A1
· McIvor et al.
· 2018
[cited by applicant]
US 20180271956A1
· McIvor et al.
· 2018
[cited by applicant]
US 20180344869A1
· Fischer et al.
· 2018
[cited by applicant]
US 20180371440A1
· Koeberl et al.
· 2018
[cited by applicant]
US 20190112588A1
· Baik et al.
· 2019
[cited by applicant]
US 20190269797A1
· Davidson et al.
· 2019
[cited by applicant]
US 20200009267A1
· Davidson et al.
· 2020
[cited by applicant]
US 20210038739A1
· Takahashi et al.
· 2021
[cited by applicant]
US 20210040464A1
· Armstrong et al.
· 2021
[cited by applicant]
US 20210040503A1
· Mingozzi et al.
· 2021
[cited by applicant]
US 20220267477A1
· Cygnar et al.
· 2022
[cited by applicant]
US 20230220100A1
· Cygnar et al.
· 2023
[cited by applicant]
EP 1716232B1
· 2010
[cited by applicant]
EP 1587923B1
· 2011
[cited by applicant]
EP 1879624B1
· 2011
[cited by applicant]
EP 2420256B1
· 2012
[cited by applicant]
EP 1620133B1
· 2015
[cited by applicant]
EP 2475376B1
· 2016
[cited by applicant]
EP 2279210B1
· 2017
[cited by applicant]
EP 2861263B1
· 2017
[cited by applicant]
EP 3315606A1
· 2018
[cited by applicant]
EP 2269658B1
· 2018
[cited by applicant]
EP 2687597B1
· 2018
[cited by applicant]
EP 3075386B1
· 2019
[cited by applicant]
EP 3292875B1
· 2020
[cited by applicant]
EP 2981551B1
· 2020
[cited by applicant]
EP 3272773B1
· 2020
[cited by applicant]
EP 3461905B1
· 2020
[cited by applicant]
KR 1020170010896
· 2017
[cited by applicant]
WO 1997005266A1
· 1997
[cited by applicant]
WO 1998016254A1
· 1998
[cited by applicant]
WO 2003057179A2
· 2003
[cited by applicant]
WO 2004023973A2
· 2004
[cited by applicant]
WO 2005077333A2
· 2005
[cited by applicant]
WO 2005092381A1
· 2005
[cited by applicant]
WO 2006108052A2
· 2006
[cited by applicant]
WO 2007024323A2
· 2007
[cited by applicant]
WO WO2007075270A1
· 2007
[cited by applicant]
WO 2008011710A1
· 2008
[cited by applicant]
WO 2008017828A2
· 2008
[cited by applicant]
WO WO2008022295A1
· 2008
[cited by applicant]
WO 2009094561A1
· 2009
[cited by applicant]
WO 2010036460A2
· 2010
[cited by applicant]
WO 2010119119A1
· 2010
[cited by applicant]
WO 2011012316A2
· 2011
[cited by applicant]
WO 2011029823A1
· 2011
[cited by applicant]
WO 2011069794A1
· 2011
[cited by applicant]
WO 2011069795A1
· 2011
[cited by applicant]
WO 2011069796A1
· 2011
[cited by applicant]
WO 2011069797A1
· 2011
[cited by applicant]
WO 2011069798A1
· 2011
[cited by applicant]
WO 2011069799A1
· 2011
[cited by applicant]
WO 2011112566A2
· 2011
[cited by applicant]
WO 2012075037A1
· 2012
[cited by applicant]
WO 2012125987A2
· 2012
[cited by applicant]
WO 2012136519A1
· 2012
[cited by applicant]
WO 2012163932A1
· 2012
[cited by applicant]
WO 2013078377A1
· 2013
[cited by applicant]
WO 2013081706A1
· 2013
[cited by applicant]
WO 2013138400A1
· 2013
[cited by applicant]
WO 2014036076A1
· 2014
[cited by applicant]
WO WO2014085621A1
· 2014
[cited by applicant]
WO 2014185908A2
· 2014
[cited by applicant]
WO 2014189973A2
· 2014
[cited by applicant]
WO 2015146132A1
· 2015
[cited by applicant]
WO 2015026907A1
· 2015
[cited by applicant]
WO 2015101588A1
· 2015
[cited by applicant]
WO 2015187596A2
· 2015
[cited by applicant]
WO 2016044947A1
· 2016
[cited by applicant]
WO 2016065319A1
· 2016
[cited by applicant]
WO 2016077840A2
· 2016
[cited by applicant]
WO 2016081640A1
· 2016
[cited by applicant]
WO 2016081643A1
· 2016
[cited by applicant]
WO 2016094566A2
· 2016
[cited by applicant]
WO WO2016085820A1
· 2016
[cited by examiner]
WO WO2016179257A2
· 2016
[cited by applicant]
WO 2016207240A1
· 2016
[cited by applicant]
WO 2017055540A1
· 2017
[cited by applicant]
WO 2017055542A1
· 2017
[cited by applicant]
WO 2017058944A1
· 2017
[cited by applicant]
WO 2017100467A2
· 2017
[cited by applicant]
WO WO2006088503A1
· 2017
[cited by applicant]
WO WO2017131496A1
· 2017
[cited by applicant]
WO WO2017134197A1
· 2017
[cited by examiner]
WO 2017186182A1
· 2017
[cited by applicant]
WO WO2017190079A1
· 2017
[cited by applicant]
WO 2017214456A1
· 2017
[cited by applicant]
WO 2017214458A2
· 2017
[cited by applicant]
WO 2017214462A2
· 2017
[cited by applicant]
WO WO2018031424A1
· 2018
[cited by applicant]
WO 2018102304A1
· 2018
[cited by applicant]
WO 2018138322A1
· 2018
[cited by applicant]
WO 2018165619A1
· 2018
[cited by applicant]
WO 2018210898A1
· 2018
[cited by applicant]
WO 2018213340A1
· 2018
[cited by applicant]
WO 2018226861A1
· 2018
[cited by applicant]
WO 2019011719A1
· 2019
[cited by applicant]
WO WO2019075417A1
· 2019
[cited by applicant]
WO 2019153009A1
· 2019
[cited by applicant]
WO 2019157224A1
· 2019
[cited by applicant]
WO 2014143909A1
· 2019
[cited by applicant]
WO WO2019197428A1
· 2019
[cited by applicant]
WO 2019222411A1
· 2019
[cited by applicant]
WO WO2019222663A1
· 2019
[cited by applicant]
WO 2020023390A1
· 2020
[cited by applicant]
WO 2020028841A1
· 2020
[cited by applicant]
WO 2020041773A1
· 2020
[cited by applicant]
WO 2020102645A1
· 2020
[cited by applicant]
WO 2020223362A1
· 2020
[cited by applicant]
WO 2020117898A1
· 2020
[cited by applicant]
WO WO2020144233A1
· 2020
[cited by applicant]
WO 2020163480A1
· 2020
[cited by applicant]
WO 2021005176A1
· 2021
[cited by applicant]
WO WO2017007796A1
· 2023
[cited by applicant]
Kishnani, P.S. (2015). Challenges of Enzyme Replacement Therapy: Poor Tissue Distribution in Lysosomal Diseases Using Pompe Disease as a Model. In: Rosenberg, A., Demeule, B. (eds) Biobetters. AAPS Advances in the Pharm…
[cited by examiner]
Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 2012;503:269-92. doi: 10.1016/B978-0-12-396962-0.00011-2. PMID: 22230573. (Year: 2015).
[cited by examiner]
Pardridge WM. Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody. Expert Opin Drug Deliv. Feb. 2015;12(2):207-22. doi: 10.1517/17425247.2014.952627. Epub Aug. 20, 20…
[cited by examiner]
Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. Oct. 2015;67(2 Pt A):95-106. doi: 10.1016/j.molimm.2015.01.003. Epub Jan. 27, 2015. PMID: 2…
[cited by examiner]
Jäger V, Büssow K, Wagner A, Weber S, Hust M, Frenzel A, Schirrmann T. High level transient production of recombinant antibodies and antibody fusion proteins in HEK293 cells. BMC Biotechnol. Jun. 26, 2013;13:52. doi: 10…
[cited by examiner]
Matsui T, Sashihara S, Oh Y, Waxman SG. An orphan nuclear receptor, mROR alpha, and its spatial expression in adult mouse brain. Brain Res Mol Brain Res. Nov. 1995;33(2):217-26. doi: 10.1016/0169-328x(95)00126-d. PMID: …
[cited by examiner]
Davies AM, Sutton BJ. Human IgG4: a structural perspective. Immunol Rev. Nov. 2015;268(1):139-59. doi: 10.1111/imr.12349. PMID: 26497518; PMCID: PMC4670484. (Year: 2015).
[cited by examiner]
Salem TZ, Seaborn CP, Turney CM, Xue J, Shang H, Cheng XW. The Influence of SV40 polyA on Gene Expression of Baculovirus Expression Vector Systems. PLoS One. Dec. 14, 2015;10(12):e0145019. doi: 10.1371/journal.pone.0145…
[cited by examiner]
Ohashi T., Enzyme replacement therapy for lysosomal storage diseases, Pediatr Endocrinol Rev, 2012, vol. 10 Suppl. 1, pp. 26-34, see the abstract.
[cited by applicant]
Ferrua F. et al., Twenty-Five Years of Gene Therapy for ADA-SCID: From Bubble Babies to an Approved Drug. Hum Gene Ther, 2017, vol. 28, N. 11, pp. 972-981, see the abstract.
[cited by applicant]
Braun S.E. et al., Preclinical studies of lymphocyte gene therapy for mild Hunter syndrome (mucopolysaccharidosis type II), Hum Gene Ther, 1996, vol. 7, N. 3, pp. 283-290, see the abstract.
[cited by applicant]
Rofo et al., “Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain,” Theranostics, 11(2):789-804, (Jan. 2021).
[cited by applicant]
Tanaka et al., “A novel approach to CNS dysfunction of Pompe disease with a fusion protein consisting of anti-transferrin receptor antibody and GAA enzyme,” Mol. Genet. Metab., 129(2):S150-S151, (Feb. 2020).
[cited by applicant]
Andrady et al., “Antibody-enzyme fusion proteins for cancer therapy,” Immunotherapy,3(2):193-211, abstract only, (Feb. 2011).
[cited by applicant]
Hofmeyer et al., “Protein production in Yarrowia lipolytica via fusion to the secreted lipase Lip2p,” Mol. Biotechnol., 56(1):79-90, (Jul. 2013).
[cited by applicant]
Jahn et al., “How to systematically evaluate immunogenicity of therapeutic proteins—regulatory considerations,” N. Biotechnol., 25(5):280-286, abstract only, (Jun. 2009).
[cited by applicant]
Ohashi, “Enzyme replacement therapy for lysosomal storage diseases,” Pediatr. Endocrinol. Rev., 10 Suppl 1:26-34, abstract only, (Oct. 2012).
[cited by applicant]
Shen et al., “Single variable domain-IgG fusion. A novel recombinant approach to Fc domain-containing bispecific antibodies,” J. Biol. Chem., 281(16):10706-10714, (Apr. 2006).
[cited by applicant]
Wingren et al., “Fusion of a signal sequence to the interleukin-1 beta gene directs the protein from cytoplasmic accumulation to extracellular release,” Cell. Immunol., 169(2):226-237, abstract only, (May 1996).
[cited by applicant]
Sun et al., “New perspectives for ERT in Pompe disease: Extending the action of the enzyme to cytosolic targets,” Molecular Genetics and Metabolism, 2016, 117:S110-S111, Abstract No. 295 doi:10.1016/j.ymgme.2015.12.453.
[cited by applicant]
Statement of Relatedness under MPEP 2001.06 with Respect to U.S. Appl. No. 16/968,452, submitted Jul. 8, 2022.
[cited by applicant]
Audran et al., “Internalization of human macrophage surface antigens induced by monoclonal antibodies,” Journal of Immunological Methods, 1995, 188:147-154.
[cited by applicant]
Azorsa, et al. “CD63/Pltgp40: A Platelet Activation Antigen Identical to the Stage-Specific Melanoma-Associated Antigen ME491,” Blood, 1991, 78(2):280-284.
[cited by applicant]
Barrio, et al. “Monoclonal Antibody FC-5.01, Directed Against CD63 Antigen, is Internalized into Cytoplasmic Vesicles in the IIB-BR-G Human Breast Cancer Cell Line,” Hybridoma, 1998, 17(6):517-525.
[cited by applicant]
Dakour, et al. “Characterization of melanosome-associated proteins by establishment of monoclonal antibodies and immunoscreening of a melanoma cDNA library through an anti-melanosome antibody,” Melanoma Research, 1993, …
[cited by applicant]
Demetrick, et al. “ME491 Melanoma-Associated Glycoprotein Family: Antigenic Identity of ME491, NKI/C-3, Neuroglandular Antigen (NGA), and CD63 Proteins,” Journal Natl. Cancer Inst., 1992; 84(6):422-429.
[cited by applicant]
Fukuda et al., “Autophagy and Mistargeting of Therapeutic Enzyme in Skeletal Muscle in Pompe Disease,” Mol. Therapy, 2006, 14(6):831-839.
[cited by applicant]
Fukuda et al., “Dysfunction of Endocytic and Autophagic Pathways in a Lysosomal Storage Disease,” Ann Neurol, 2006, 59(4):700-708.
[cited by applicant]
Hořejši and Vlček “Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63,” FEBS, Aug. 1991, 288(1,2):1-4.
[cited by applicant]
Israels and McMillan-Ward, “CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen,” Thromb. Haemost., 2005, 93(2):311-318.
[cited by applicant]
Kennel, et al., “Monoclonal Antibody to Rat CD63 Detects Different Molecular Form in Rat Tissue,” Hybridoma, 1998, 17(6):509-515.
[cited by applicant]
Knol, et al. “Monitoring human basophil activation via CD63 monoclonal antibody 435,” J. Allergy Clin. Immunol., 1991, 88(3, Part 1):328-338.
[cited by applicant]
Kraft et al., “Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo,” JEM, 2005, 201(3):385-396.
[cited by applicant]
Lee et al., “Novel strategy for a bispecific antibody: induction of dual target internalization and degradation,” Oncogene, 2016, 35(34):4437-4446.
[cited by applicant]
Moody et al., “Receptor Crosslinking: A General Method to Trigger Internalization and Lysosomal Targeting of Therapeutic Receptor: Ligand Complexes,” Molecular Therapy, 2015, 23(12):1888-1898.
[cited by applicant]
Pacak et al. “Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice,” Genetic Vaccines and Therapy, 2008 6:13 (5 pages).
[cited by applicant]
Valadi et al., “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells,” Nature Cell Biology, Jun. 2007, 9(6):654-659 and Supplementary Information (18 pages).
[cited by applicant]
Verjan Garcia, et al., “SIRPa/CD172a Regulates Eosinophil Homeostasis,” Journal of Immunology, 2011, 187:2268-2277.
[cited by applicant]
Vischer and Wagner, “CD63 Is a Component of Weibel-Palade Bodies of Human Endothelial Cells,” Blood, 1993, 82(4):1184-1191.
[cited by applicant]
Statement of Relatedness under MPEP 2001.06 with Respect to U.S. Appl. No. 16/968,452 dated Aug. 17, 2022.
[cited by applicant]
Author Unknown, The Journal of the Japanese Society of Internal Medicine, (2009) vol. 98, No. 4, p. 875-882, submitted with the English Translation of Office Action dated Mar. 24, 2022 with respect to JP 2019-567722.
[cited by applicant]
Baik et al., “Engineering tissue specific delivery of enzymes for lysosomal disease treatment,” Abstracts, Molecular Genetics and Metabolism, 2016, 120:S23-S24.
[cited by applicant]
Ozawa, K., “Gene therapy using AAV,” Virus, (2007) vol. 57, No. 1, p. 47-56 (includes English translation).
[cited by applicant]
Van Der Ploeg and Reuser “Lysosomal Storage Disease 2,” Lancet, 2008, 372:1342-1353.
[cited by applicant]
Office Action Mar. 24, 2022 English Translation of Office Action with respect to JP 2019-567722.
[cited by applicant]
Statement of Relatedness under MPEP 2001.06 with Respect to U.S. Appl. No. 16/968,452 dated Apr. 21, 2022.
[cited by applicant]
Ahmad et al., “scFv Antibody: Principles and Clinical Application,” Clinical and Developmental Immunology, vol. 2012, article ID 980250, 15 pages.
[cited by applicant]
Andreev et al., “Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs,” Mol. Cancer Ther., Apr. 2017, 16(4):681-693.
[cited by applicant]
Anzai et al., “c-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors,” Blood, 2002, 99(12):4413-4421, doi:10.1182/blood.V99.12.4413.
[cited by applicant]
Arai et al., “Design of the linkers which effectively separate domains of a bifunctional fusion protein,” Protein Engineering, 2001, 14(8):529-532.
[cited by applicant]
Arnold et al. “Metabolic Biotinylation Provides a Unique Platform for the Purification and Targeting of Multiple AAV Vector Serotypes,” Molecular Therapy, 2006, 14(1):97-106.
[cited by applicant]
Arribas and Cutler, “Weibel-Palade Body Membrane Proteins Exhibit Differential Trafficking After Exocytosis in Endothelial Cells,” Traffic, 2000, 1:783-793.
[cited by applicant]
Aurnhammer et al., “Universal Real-Time PCR for the Detection and Quantification of Adeno-Associated Virus Serotype 2-Derived Inverted Terminal Repeat Sequences,” Hum. Gene Ther. Methods, Part B, 2012, 23:18-28.
[cited by applicant]
Baik et al., “Next-generation antibody-guided enzyme replacement therapy in Pompe disease mice,” Molecular Genetics and Metabolism, 2018, 123(2):S21 Abstract Only.
[cited by applicant]
Baik, et al., “Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice,” Biorxiv, Apr. 23, 2020; retrieved from the internet Nov. 3, 2020 https://www.biorxiv.org/content/10.…
[cited by applicant]
Banerjee et al., “Targeted and armed oncolytic adenovirus via chemoselective modification,” Bioorganic and Medicinal Chemistry Letters, 2011, 21(17):4985-4988.
[cited by applicant]
Bareford and Swaan, “Endocytic mechanisms for targeted drug delivery,” Advanced Drug Delivery Reviews, Elsevier, Amsterdam, NL, 2007, 59(8):748-758.
[cited by applicant]
Bartlett et al., “Infectious Entry Pathway of Adeno-Associated Virus and Adeno-Associated Virus Vectors,” Journal of Virology, 2000, 74(6):2777-2785.
[cited by applicant]
Barzel et al., “Promoterless gene targeting without nucleases ameliorates hemophilia B in mice,” Nature, 2015, 517(7534):360-364.
[cited by applicant]
Battig et al., “Programmable Release of Multiple Protein Drugs from Aptamer-Functionalized Hydrogels via Nucleic Acid Hybridization,” J. Am. Chem. Society., 2012, 134:12410-12413.
[cited by applicant]
Beatty, “Trafficking from CD63-positive late endocytic multivesicular bodies is essential for intracellular development of
[cited by applicant]
Bedinger et al., “Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody,” Journal of Pharmacology and Experimental Therapeutics, 20…
[cited by applicant]
Berditchevski et al., “Specific Association of CD63 with the VLA-3 and VLA-6 Integrins,” Journal of Biological Chemistry, 1995, 270(30):17784-17790.
[cited by applicant]
Berditchevski et al., “Characterization of Novel Complexes on the Cell Surface between Integrins and Proteins with 4 Transmembrane Domains (TM4 proteins),” Molecular Biology of the Cell, 1996, 7:193-207.
[cited by applicant]
Berditchevski et al., “A Novel Link between Integrins, Transmembrane-4 Superfamily Proteins (CD63 and CD81), and Phosphatidylinositol 4-Kinase*,” Journal of Biological Chemistry, Jan. 1997, 272(5):2595-2598.
[cited by applicant]
Berditchevski et al., “Generation of Monoclonal Antibodies to Integrin-associated Proteins,” Journal of Biological Chemistry, Nov. 1997, 272(46):29174-29180.
[cited by applicant]
Berditchevski et al., “Expression of the Palmitoylation-deficient CD151 Weakens the Association of α3β1 Integrin with the Tetraspanin-enriched Microdomains and Affects Integrin-dependent Signaling*,” Journal of Biologic…
[cited by applicant]
Berger et al., “Fusion protein technologies for biopharmaceuticals: Applications and challenges,” mAbs, 2015, 7(3):456-460.
[cited by applicant]
Bezwada et al., “A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys,” Journal of Pharmacology and Experimental Therapeutics, 2016, 356(2):46…
[cited by applicant]
Bian et al., “Selective gene transfer in vitro to tumor cells via recombinant Newcastle disease virus,” Cancer Gene Ther., 2005, 12:295-303.
[cited by applicant]
Bian et al., “In vivo efficacy of systemic tumor targeting of a viral RNA vector with oncolytic properties using a bispecific adapter protein,” Int. J. Oncol., 2006, 29:1359-1369.
[cited by applicant]
Bixby et al. “A Phase I Study of IGN523, a Novel Anti-CD98 Monoclonal Antibody in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML),” Blood, 2015, 126(23):3809.
[cited by applicant]
Blechacz and Russell, “Measles Virus as an Oncolytic Vector Platform,” Current Gene Therapy, 2008, 8:162-175.
[cited by applicant]
Boado et al., “Genetic Engineering of a Lysosomal Enzyme Fusion Protein for Targeted Delivery Across the Human Blood-Brain Barrier,” Biotechnology and Bioengineering, Feb. 1, 2008, 99(2):475-484.
[cited by applicant]
Boado et al., “IgG-Enzyme Fusion Protein: Pharmacokinetics and Anti-Drug Antibody Response in Rhesus Monkeys,” Bioconjugate Chemistry, 2013, 24(1):97-104.
[cited by applicant]
Boado et al, “Insulin Receptor Antibody-Sulfamidase Fusion Protein Penetrates the Primate Blood-Brain Barrier and Reduces Glycosoaminoglycans in Sanfilippo Type A Cells,” Mol Pharm. 11(8):2928-2934 (Aug. 4, 2014).
[cited by applicant]
Boado et al., “Very High Plasma Concentrations of a Monoclonal Antibody against the Human Insulin Receptor Are Produced by Subcutaneous Injection in the Rhesus Monkey,” Mol. Pharmaceutics, 2016, 13(9):3241-3246.
[cited by applicant]
Boado et al., “Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse,” Molecular Pharmaceutics, 2018, 15:602-608.
[cited by applicant]
Bode et al., “Antibody-Directed Fibrinolysis: An Antibody Specific for Both Fibrin and Tissue Plasminogen Activator,” Journal of Biological Chemistry, Jan. 1989, 264(2):944-948.
[cited by applicant]
Bonardi et al., “Delivery of Saporin to Human B-Cell Lymphoma Using Bispecific Antibody: Targeting via CD22 but not CD19, CD37, or Immunoglobulin Results in Efficient Killing,” Cancer Research, Jul. 1993, 53(13):3015-30…
[cited by applicant]
Boustany, “Lysosomal storage diseases—the horizon expands,” Nat. Rev. Neurol., Oct. 2013, 9(10):583-598.
[cited by applicant]
Cabezon et al., “Trafficing of Gold Nanoparticles Coated with the 8D3 Anti-Transferrin Receptor Antibody at the Mouse Blood-Brain Barrier,” Molecular Pharmaceutics, 2015, 12(11),4137-4145 DOI: 10.1021/acs.molpharmaceut.…
[cited by applicant]
Campadelli-Fiume et al., “Rethinking herpes simplex virus: the way to oncolytic agents,” Reviews in Medical Virology, 2011, 21:213-226.
[cited by applicant]
Catelas et al., “Controlled Release of Bioactive Transforming Growth Factor Beta-1 from Fibrin Gels In Vitro,” Tissue Engineering: Part C, 2008, 14(2):119-128.
[cited by applicant]
Chadwick et al., “Modification of Retroviral Tropism by Display of IGF-I,” Journal of Molecular Biology, 1999, 285:485-494.
[cited by applicant]
Chen et al., “Fusion Protein Linkers: Property, Design and Functionality,” Adv Drug Deliv Rev., 2013, 65(10):1357-1369.
[cited by applicant]
Chiba, “Molecular Mechanism in α-Glucosidase and Glucoamylase,” Biosci. Biotechnol. Biochem., 1997, 61(8):1233-1239.
[cited by applicant]
Chuah et al., “Liver-Specific Transcriptional Modules Identified by Genome-Wide In Silico Analysis Enable Efficient Gene Therapy in Mice and Non-Human Primates,” Mol. Ther., 2014, 22(9):1605-1613.
[cited by applicant]
Cieniewicz et al., “Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance,” Diabetes, 2017, 66(1):206-217.
[cited by applicant]
Clevenger and Kline, “Prolactin receptor signal transduction,” 10(10) Lupus, (2001) 10:706-718.
[cited by applicant]
Corti et al., “Safety of Intradiaphragmatic Delivery of Adeno-Associated Virus-Mediated Alpha-Glucosidase (rAAV1-CMV-hGAA) Gene Therapy in Children Affected by Pompe Disease,” Human Gene Therapy Clinical Development, 20…
[cited by applicant]
Couch et al. “Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier,” Science Translational Medicine, 2013, vol. 5, Issue 183, pp. 183ra57 DOI: 10.1126/scitranslmed.3005338.
[cited by applicant]
Dalba et al., “Beyond Oncolytic Virotherapy: Replication-Competent Retrovirus Vectors for Selective and Stable Transduction of Tumors,” Current Gene Therapy, 2005, 5:655-667.
[cited by applicant]
Darvish-Damavandi et al., “Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia,” Molecular Genetics and Metabolism Reports, 2016, 8(1):51-60.
[cited by applicant]
De Goeij et al., “Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63,” Mol. Cancer Ther., 2016, 15(11):2688-2697.
[cited by applicant]
Derosa et al., “Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system,” Gene Therapy, 2016, 23:699-707.
[cited by applicant]
Desnick and Schuchman, “Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges,” 13 Annu. Rev. Genomics Hum. Genet., 2012, 13:307-335.
[cited by applicant]
Dhital et al., “Mammalian Mucosal α-Glucosidases Coordinate with α-Amylase in the Initial Starch Hydrolysis Stage to Have a Role in Starch Digestion Beyond Glucogenesis,” PLoS One, 2013, 8(4):e62546, 13 pages.
[cited by applicant]
Dimauro and Spiegel, “Progress and problems in muscle glycogenosis,” Acta Myologica, Oct. 2011, 30(2):96-102.
[cited by applicant]
Doyle et al., “CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin,” Blood, 2011, 118(15):4265-427.
[cited by applicant]
Duffield et al., “The tetraspanin CD63 enhances the internalization of the H,K-ATPase β-subunit,” Proc. Nail. Acad. Sci. USA, Dec. 2003, 100(26):15560-15565.
[cited by applicant]
Egea et al., “Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling,” PNAS, 2012, 109(6):E309-E316.
[cited by applicant]