HRP20200583T1 - Protutijela koja neutraliziraju gp120 i njihova upotreba - Google Patents
Protutijela koja neutraliziraju gp120 i njihova upotreba Download PDFInfo
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- HRP20200583T1 HRP20200583T1 HRP20200583TT HRP20200583T HRP20200583T1 HR P20200583 T1 HRP20200583 T1 HR P20200583T1 HR P20200583T T HRP20200583T T HR P20200583TT HR P20200583 T HRP20200583 T HR P20200583T HR P20200583 T1 HRP20200583 T1 HR P20200583T1
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- 230000003472 neutralizing effect Effects 0.000 title 1
- 239000012634 fragment Substances 0.000 claims 16
- 239000000427 antigen Substances 0.000 claims 15
- 108091007433 antigens Proteins 0.000 claims 15
- 102000036639 antigens Human genes 0.000 claims 15
- 150000007523 nucleic acids Chemical class 0.000 claims 15
- 102000039446 nucleic acids Human genes 0.000 claims 14
- 108020004707 nucleic acids Proteins 0.000 claims 14
- 125000003275 alpha amino acid group Chemical group 0.000 claims 13
- 210000004027 cell Anatomy 0.000 claims 9
- 239000013604 expression vector Substances 0.000 claims 8
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 6
- 208000031886 HIV Infections Diseases 0.000 claims 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 4
- 210000004602 germ cell Anatomy 0.000 claims 4
- 238000000034 method Methods 0.000 claims 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 239000013603 viral vector Substances 0.000 claims 3
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims 2
- -1 host cell Substances 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 108090000623 proteins and genes Proteins 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- 208000037357 HIV infectious disease Diseases 0.000 claims 1
- 101001138121 Homo sapiens Immunoglobulin kappa variable 1-33 Proteins 0.000 claims 1
- 101001047617 Homo sapiens Immunoglobulin kappa variable 3-11 Proteins 0.000 claims 1
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 claims 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 claims 1
- 102100020901 Immunoglobulin kappa variable 1-33 Human genes 0.000 claims 1
- 102100022955 Immunoglobulin kappa variable 3-11 Human genes 0.000 claims 1
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 claims 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 1
- 239000012472 biological sample Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims 1
- 230000016784 immunoglobulin production Effects 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- 108010068617 neonatal Fc receptor Proteins 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
- C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
- G01N33/56988—HIV or HTLV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
- G01N2333/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
- G01N2333/16—HIV-1, HIV-2
- G01N2333/162—HIV-1, HIV-2 env, e.g. gp160, gp110/120, gp41, V3, peptid T, DC4-Binding site
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/26—Infectious diseases, e.g. generalised sepsis
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- Genetics & Genomics (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Claims (22)
1. Izolirano monoklonsko protutijelo, naznačeno time sadrži:
varijabilno područje teškog lanca (VH), koje sadrži područja određivanja komplementarnosti teškog lanca HCDR1, HCDR2, te HCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 7, 8 odnosno 9, i varijabilno područje lakog lanca (VL), koje sadrži područja određivanja komplementarnosti lakog lanca LCDR1, LCDR2, te LCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 10, 11 odnosno 12 (N6 CDR);
VH, koji sadrži HCDR1, HCDR2, te HCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 13, 14, i 15, odnosno, i VL, koje sadrži LCDR1, LCDR2, te LCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 16, 17 odnosno 18 (N17 CDR); ili
VH, koji sadrži HCDR1, HCDR2, te HCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 7, 8 odnosno 9, i VL, koji sadrži LCDR1, LCDR2, te LCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 10, 17 odnosno 18 (F8 CDR); i
gdje se protutijelo specifično veže na gp120 iz virusa HIV-1 i neutralizira zarazu virusom HIV-1.
2. Izolirano monoklonsko protutijelo u skladu s patentnim zahtjevom 1, naznačeno time što sadrži varijabilno područje teškog lanca (VH), koje sadrži područja određivanja komplementarnosti teškog lanca HCDR1, HCDR2, te HCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 7, 8 odnosno 9, i varijabilno područje lakog lanca (VL), koje sadrži područja određivanja komplementarnosti lakog lanca LCDR1, LCDR2, te LCDR3, koja imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 10, 11 odnosno 12 (N6 CDR).
3. Izolirano monoklonsko protutijelo u skladu s patentnim zahtjevom 2, naznačeno time što VH i VL imaju aminokiselinske sljedove najmanje 90% istovjetne SEQ ID NO: 1 odnosno 2 (N6 mAb).
4. Izolirano monoklonsko protutijelo u skladu s patentnim zahtjevom 3, naznačeno time što VH i VL imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 1 odnosno 2 (N6 mAb).
5. Izolirano monoklonsko protutijelo u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeno time što
VH i VL imaju aminokiselinske sljedove najmanje 90% istovjetne SEQ ID NO: 3 odnosno 4 (N17 mAb), ili SEQ ID NO: 5 odnosno 6 (F8 mAb).
6. Izolirano monoklonsko protutijelo u skladu s patentnim zahtjevom 5, naznačeno time što
VH i VL imaju aminokiselinske sljedove kao što su iznijeti u SEQ ID NO: 3 odnosno 4 (N17 mAb), ili SEQ ID NO: 5 odnosno 6 (F8 mAb).
7. Izolirano monoklonsko protutijelo u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeno time što
VH sadrži arginin ostatak na položaju 71 prema Kabatu,
VH ima podrijetlo iz zametne linije VH1-2 koje se od 20-35% razlikuje od gena iz zametne linije; i
VL ima podrijetlo iz zametne linije IGKV3-11, IGKV3-20, IGKV1-33 ili IGLV2 koje se od 15-35% razlikuje od odgovarajućeg gena iz zametne linije.
8. Izolirano monoklonsko protutijelo u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeno time što sadrži ljudsko područje okosnice i/ili
što je protutijelo IgG, IgM ili IgA, osobito kada je protutijelo IgG i sadrži teški lanac koji ima aminokiselinski slijed kao što je iznijet u SEQ IDNO: 94 i/ili
što sadrži rekombinantnu konstantnu domenu, koja ima modifikaciju koja povećava vezanje na novorođenački receptor Fc,
osobito kada je rekombinantna konstantna domena IgG1 konstantna domena koja sadrži mutacije M428L i N434S.
9. Antigenski vežući fragment koji sadrži VH i VL izoliranog monoklonskog protutijela u skladu s bilo kojim od patentnih zahtjeva 1-7, naznačen time što je antigenski vežući fragment fragment Fv, Fab, F(ab’)2, scFV ili scFV2.
10. Izolirano monoklonsko protutijelo ili antigenski vežući fragment u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeno time što se protutijelo ili antigenski vežući fragment specifično veže na mjesto za vezanje na CD4 u gp120, i/ili
što protutijelo ili antigenski vežući fragment neutralizira najmanje 50% izolata virusa HIV-1 iznijetih kao 6540.v4.c1, 620345.c1, T278-50, 6322.V4.C1, DU422.01, X2088.c9, 6545.V4.C1, 242-14, T250-4, 7165.18, BL01.DG, HO86.8, 6471.V1.C16, 6631.V3.C10, TVI.29, TZA125.17, CAP210.E8, DU172.17 s inhibicijskom koncentracijom (IC50) od <50 µg/ml.
11. Izolirano bispecifično protutijelo, naznačeno time što sadrži izolirano ljudsko monoklonsko protutijelo ili antigenski vežući fragment u skladu s bilo kojim od prethodnih patentnih zahtjeva, osobito kada se protutijelo specifično veže na gp120 i na CD3.
12. Izolirana molekula nukleinske kiseline, naznačena time što kodira protutijelo ili antigenski vežući fragment u skladu s bilo kojim od patentnih zahtjeva 1-11.
13. Izolirana molekula nukleinske kiseline u skladu s patentnim zahtjevom 12, naznačena time što nukleinskokiselinski sljedovi, kao što su iznijeti u SEQ ID NO: 36 odnosno 37 (N6 mAb), ili njihove degenerirane varijante, kodiraju VH i VL protutijela ili antigenski vežućeg fragmenta.
14. Izolirana molekula nukleinske kiseline u skladu s patentnim zahtjevom 12 ili patentnim zahtjevom 13, naznačena time što kodira kimerni antigenski receptor, koji sadrži izvanstaničnu domenu, gdje izvanstanična domena sadrži antigenski vežući fragment kojeg kodira molekula nukleinske kiseline, te što nukleinska kiselina dodatno kodira kimerni antigenski receptor.
15. Ekspresijski vektor, naznačen time što sadrži molekulu nukleinske kiseline u skladu s patentnim zahtjevom 12-14, osobito kada je ekspresijski vektor virusni vektor, osobito kada je virusni vektor adeno-asocirani virusni vektor.
16. Izolirana stanica domaćin, naznačena time što je transformirana molekulom nukleinske kiseline ili ekspresijskim vektorom u skladu s bilo kojim od patentnih zahtjeva 12-15.
17. Farmaceutski pripravak namijenjen upotrebi u liječenje zaraze virusom HIV-1, naznačen time što sadrži:
terapijski djelotvornu količinu protutijela, antigenski vežućeg fragmenta, molekule nukleinske kiseline, ekspresijskog vektora, ili stanica domaćin u skladu s bilo kojim od patentnih zahtjeva 1-16; i
farmaceutski prihvatljivi nosač.
18. Postupak proizvodnje protutijela koje se specifično veže na gp120 iz virusa HIV-1, naznačen time što se sastoji u:
eksprimiranju heterologne molekule nukleinske kiseline koji sadrži molekulu nukleinske kiseline u skladu s bilo kojim od patentnih zahtjeva 12-14 u stanici domaćinu radi proizvodnje protutijela,
osobito kada je stanica domaćin sisavačka stanica domaćin i/ili
što se dodatno sastoji u pročišćavanju protutijela koje se specifično veže na gp120 iz virusa HIV-1.
19. Postupak detektiranja zaraze virusom HIV-1 kod subjekta, naznačen time što se sastoji u:
stavljanju u kontakt biološkog uzorka iz subjekta s protutijelom ili antigenski vežućim fragmentom u skladu s bilo kojim od patentnih zahtjeva 1-11 u uvjetima dovoljnima za stvaranje imunosnog kompleksa; i
detektiranju prisutnosti imunosnog kompleksa u uzorku, gdje prisutnost imunosnog kompleksa u uzorku ukazuje da je subjekt zaražen virusom HIV-1.
20. Terapijski djelotvorna količina protutijela, antigenski vežućeg fragmenta, molekule nukleinske kiseline, ekspresijskog vektora, stanice domaćina, ili farmaceutskog pripravka u skladu s bilo kojim od patentnih zahtjeva 1-17, naznačena time što je namijenjena upotrebi u postupku sprječavanja ili liječenja zaraze virusom HIV-1 kod subjekta, koja se sastoji u primjeni na subjektu terapijski djelotvorne količine protutijela, antigenski vežućeg fragmenta, molekule nukleinske kiseline, ekspresijskog vektora, stanice domaćina, ili farmaceutskog pripravka u skladu s bilo kojim od patentnih zahtjeva 1-17, čime se sprječava ili liječi zarazu virusom HIV-1.
21. Komplet, naznačen time što sadrži spremnik koji sadrži protutijelo, antigenski vežući fragment, molekulu nukleinske kiseline, ekspresijski vektor, stanicu domaćina, ili farmaceutskog pripravka u skladu s bilo kojim od patentnih zahtjeva 1-17, te upute o upotrebi kompleta.
22. Protutijelo, antigenski vežući fragment, molekula nukleinske kiseline, ekspresijski vektor, stanica domaćin, ili farmaceutski pripravak u skladu s bilo kojim od patentnih zahtjeva 1-17, naznačeno time što je namijenjeno upotrebi u inhibiranju ili liječenju zaraze virusom HIV-1 kod subjekta.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562136228P | 2015-03-20 | 2015-03-20 | |
US201562250378P | 2015-11-03 | 2015-11-03 | |
PCT/US2016/023145 WO2016154003A1 (en) | 2015-03-20 | 2016-03-18 | Neutralizing antibodies to gp120 and their use |
EP16716979.6A EP3271389B8 (en) | 2015-03-20 | 2016-03-18 | Neutralizing antibodies to gp120 and their use |
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HRP20200583T1 true HRP20200583T1 (hr) | 2020-07-10 |
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HRP20200583TT HRP20200583T1 (hr) | 2015-03-20 | 2020-04-10 | Protutijela koja neutraliziraju gp120 i njihova upotreba |
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US (4) | US10562960B2 (hr) |
EP (2) | EP3271389B8 (hr) |
CN (1) | CN108137676B (hr) |
AU (1) | AU2016235541B2 (hr) |
CA (1) | CA2980005A1 (hr) |
CY (1) | CY1123068T1 (hr) |
DK (1) | DK3271389T3 (hr) |
ES (1) | ES2789348T3 (hr) |
HR (1) | HRP20200583T1 (hr) |
HU (1) | HUE049081T2 (hr) |
LT (1) | LT3271389T (hr) |
PL (1) | PL3271389T3 (hr) |
PT (1) | PT3271389T (hr) |
RS (1) | RS60270B1 (hr) |
SI (1) | SI3271389T1 (hr) |
WO (1) | WO2016154003A1 (hr) |
ZA (1) | ZA201706155B (hr) |
Families Citing this family (32)
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JP7492336B2 (ja) | 2016-10-21 | 2024-05-29 | アルター・バイオサイエンス・コーポレーション | 多量体il-15に基づく分子 |
EP3642229A1 (en) * | 2017-06-21 | 2020-04-29 | Gilead Sciences, Inc. | Multispecific antibodies that target hiv gp120 and cd3 |
EP3641806A4 (en) | 2017-06-22 | 2021-06-23 | University of Maryland, Baltimore | BROAD NEUTRALIZING ANTIBODIES AGAINST HIV |
CN107098969B (zh) * | 2017-06-28 | 2018-10-12 | 武汉波睿达生物科技有限公司 | 一种治疗hiv感染的嵌合抗原受体的重组基因构建及其应用 |
US20230070158A1 (en) * | 2017-10-23 | 2023-03-09 | City Of Hope | CAR for Treatment of HIV Infection |
AU2019226034A1 (en) | 2018-02-21 | 2020-10-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to HIV-1 Env and their use |
EP3762033A4 (en) * | 2018-03-09 | 2021-12-08 | Atreca, Inc. | ANTI-HIV ANTIBODIES |
CN112334572A (zh) | 2018-06-19 | 2021-02-05 | 南特细胞公司 | Hiv治疗组合物和方法 |
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LT3271389T (lt) | 2020-05-25 |
EP3271389A1 (en) | 2018-01-24 |
ZA201706155B (en) | 2022-05-25 |
CN108137676B (zh) | 2022-03-15 |
US20230060304A1 (en) | 2023-03-02 |
CY1123068T1 (el) | 2020-11-25 |
EP3271389B1 (en) | 2020-02-12 |
PT3271389T (pt) | 2020-05-13 |
HUE049081T2 (hu) | 2020-09-28 |
US20180298083A1 (en) | 2018-10-18 |
EP3683233A1 (en) | 2020-07-22 |
RS60270B1 (sr) | 2020-06-30 |
AU2016235541B2 (en) | 2021-04-01 |
US20200231658A1 (en) | 2020-07-23 |
PL3271389T3 (pl) | 2020-08-10 |
CA2980005A1 (en) | 2016-09-29 |
SI3271389T1 (sl) | 2020-09-30 |
WO2016154003A8 (en) | 2016-10-27 |
EP3271389B8 (en) | 2020-04-22 |
ES2789348T3 (es) | 2020-10-26 |
US20210324053A1 (en) | 2021-10-21 |
AU2016235541A1 (en) | 2017-09-28 |
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