JP2020521478A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2020521478A5 JP2020521478A5 JP2019565865A JP2019565865A JP2020521478A5 JP 2020521478 A5 JP2020521478 A5 JP 2020521478A5 JP 2019565865 A JP2019565865 A JP 2019565865A JP 2019565865 A JP2019565865 A JP 2019565865A JP 2020521478 A5 JP2020521478 A5 JP 2020521478A5
- Authority
- JP
- Japan
- Prior art keywords
- isvd
- seq
- polypeptide
- lrp5
- sequence
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 claims 43
- 229920001184 polypeptide Polymers 0.000 claims 36
- 102000004196 processed proteins & peptides Human genes 0.000 claims 36
- 230000027455 binding Effects 0.000 claims 25
- 102000009027 Albumins Human genes 0.000 claims 13
- 108010088751 Albumins Proteins 0.000 claims 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 10
- 102000052547 Wnt-1 Human genes 0.000 claims 7
- 108700020987 Wnt-1 Proteins 0.000 claims 7
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 108090000623 proteins and genes Proteins 0.000 claims 6
- 230000035897 transcription Effects 0.000 claims 6
- 238000013518 transcription Methods 0.000 claims 6
- 108060003951 Immunoglobulin Proteins 0.000 claims 5
- 206010028980 Neoplasm Diseases 0.000 claims 5
- 239000003814 drug Substances 0.000 claims 5
- 102000018358 immunoglobulin Human genes 0.000 claims 5
- 101001039199 Homo sapiens Low-density lipoprotein receptor-related protein 6 Proteins 0.000 claims 4
- 102000008100 Human Serum Albumin Human genes 0.000 claims 4
- 108091006905 Human Serum Albumin Proteins 0.000 claims 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims 4
- 239000012581 transferrin Substances 0.000 claims 4
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- 102100040704 Low-density lipoprotein receptor-related protein 6 Human genes 0.000 claims 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 2
- 208000017442 Retinal disease Diseases 0.000 claims 2
- 206010038923 Retinopathy Diseases 0.000 claims 2
- 102000004338 Transferrin Human genes 0.000 claims 2
- 108090000901 Transferrin Proteins 0.000 claims 2
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims 2
- 230000033115 angiogenesis Effects 0.000 claims 2
- 239000002246 antineoplastic agent Substances 0.000 claims 2
- 229940022399 cancer vaccine Drugs 0.000 claims 2
- 238000009566 cancer vaccine Methods 0.000 claims 2
- 210000004027 cell Anatomy 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 229940127089 cytotoxic agent Drugs 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 229940121647 egfr inhibitor Drugs 0.000 claims 2
- 239000013604 expression vector Substances 0.000 claims 2
- 239000012634 fragment Substances 0.000 claims 2
- 102000055436 human LRP6 Human genes 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 2
- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 229920001223 polyethylene glycol Polymers 0.000 claims 2
- 230000019491 signal transduction Effects 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 101001043594 Homo sapiens Low-density lipoprotein receptor-related protein 5 Proteins 0.000 claims 1
- 102000007330 LDL Lipoproteins Human genes 0.000 claims 1
- 108010007622 LDL Lipoproteins Proteins 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 101710196169 Receptor-like protein 5 Proteins 0.000 claims 1
- 206010039491 Sarcoma Diseases 0.000 claims 1
- 102000013814 Wnt Human genes 0.000 claims 1
- 108050003627 Wnt Proteins 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 210000004443 dendritic cell Anatomy 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 1
- 230000003054 hormonal effect Effects 0.000 claims 1
- 238000001794 hormone therapy Methods 0.000 claims 1
- 102000055426 human LRP5 Human genes 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 230000002584 immunomodulator Effects 0.000 claims 1
- 229940121354 immunomodulator Drugs 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 230000000116 mitigating effect Effects 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000011664 signaling Effects 0.000 claims 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17173782.8 | 2017-05-31 | ||
| EP17173782 | 2017-05-31 | ||
| PCT/EP2018/064295 WO2018220080A1 (en) | 2017-05-31 | 2018-05-30 | Polypeptides antagonizing wnt signaling in tumor cells |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2020521478A JP2020521478A (ja) | 2020-07-27 |
| JP2020521478A5 true JP2020521478A5 (enExample) | 2021-07-26 |
| JP7216024B2 JP7216024B2 (ja) | 2023-01-31 |
Family
ID=59021278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019565865A Active JP7216024B2 (ja) | 2017-05-31 | 2018-05-30 | 腫瘍細胞におけるＷｎｔシグナル伝達と拮抗するポリペプチド |
Country Status (26)
| Country | Link |
|---|---|
| US (3) | US11033636B2 (enExample) |
| EP (1) | EP3630816B1 (enExample) |
| JP (1) | JP7216024B2 (enExample) |
| KR (1) | KR102717656B1 (enExample) |
| CN (1) | CN110637030B (enExample) |
| AR (1) | AR111840A1 (enExample) |
| AU (1) | AU2018276409B2 (enExample) |
| BR (1) | BR112019022729A2 (enExample) |
| CA (1) | CA3060401A1 (enExample) |
| CL (1) | CL2019003419A1 (enExample) |
| CO (1) | CO2019012329A2 (enExample) |
| EA (1) | EA201992808A1 (enExample) |
| ES (1) | ES2979194T3 (enExample) |
| HU (1) | HUE067691T2 (enExample) |
| IL (1) | IL270854B2 (enExample) |
| MA (1) | MA48760A (enExample) |
| MX (1) | MX2019014331A (enExample) |
| MY (1) | MY200744A (enExample) |
| NZ (1) | NZ758031A (enExample) |
| PE (1) | PE20200610A1 (enExample) |
| PH (1) | PH12019502602A1 (enExample) |
| PL (1) | PL3630816T3 (enExample) |
| TW (1) | TWI887192B (enExample) |
| UA (1) | UA125761C2 (enExample) |
| WO (1) | WO2018220080A1 (enExample) |
| ZA (1) | ZA201906610B (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11033636B2 (en) * | 2017-05-31 | 2021-06-15 | Boehringer Ingelheim International Gmbh | Polypeptides antagonizing Wnt signaling in tumor cells |
| WO2019032628A1 (en) | 2017-08-07 | 2019-02-14 | The Regents Of The University Of California | GENERATING PLATFORM FOR SAFE CELLULAR THERAPEUTIC AGENTS |
| CN111699003B (zh) | 2017-12-19 | 2024-05-03 | 瑟罗泽恩奥普瑞汀公司 | 抗lrp5/6抗体和使用方法 |
| JP7418332B2 (ja) | 2017-12-19 | 2024-01-19 | スロゼン オペレーティング， インコーポレイテッド | 抗フリズルド抗体及び使用方法 |
| CN118271444A (zh) | 2017-12-19 | 2024-07-02 | 瑟罗泽恩奥普瑞汀公司 | Wnt替代分子和其用途 |
| WO2020080941A1 (en) * | 2018-10-16 | 2020-04-23 | Umc Utrecht Holding B.V. | Anti- low-density lipoprotein receptor-related protein 5/6 antibodies |
| AU2020221797A1 (en) * | 2019-02-11 | 2021-08-12 | Surrozen Operating, Inc. | Modulation of WNT signalling in ocular disorders |
| US11578129B2 (en) * | 2019-03-29 | 2023-02-14 | Boehringer Ingelheim International Gmbh | LRP5 and PD-1 antagonist anticancer combination therapy |
| US20230183336A1 (en) * | 2019-08-14 | 2023-06-15 | Modmab Therapeutics Inc. | Antibodies that bind to lrp5 proteins and methods of use |
| WO2023250402A2 (en) * | 2022-06-22 | 2023-12-28 | Antlera Therapeutics Inc. | Tetravalent fzd and wnt co-receptor binding antibody molecules and uses thereof |
| KR102920873B1 (ko) * | 2021-07-13 | 2026-02-02 | 인제대학교 산학협력단 | NEURL 유전자, 이를 포함하는 발현벡터 또는 NEURL 단백질을 유효성분으로 포함하는 β-카테닌 과발현으로 인한 암질환 예방 또는 치료용 약학조성물 |
| CN117897408A (zh) * | 2021-08-10 | 2024-04-16 | 热生物制品有限公司 | 新型tim-4结合剂的生成和表征 |
| CN114702588B (zh) * | 2022-04-27 | 2022-11-22 | 博际生物医药科技(杭州)有限公司 | 抗Nectin-4抗体和双特异性抗体 |
| CN120424217B (zh) * | 2025-04-30 | 2026-03-06 | 立凌生物制药(苏州)有限公司 | 靶向b细胞抗原和t细胞抗原的多特异性抗体及其应用 |
Family Cites Families (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69334275D1 (de) | 1992-08-21 | 2009-05-20 | Univ Bruxelles | Immunoglobuline ohne Leichtkette |
| EP0739981A1 (en) | 1995-04-25 | 1996-10-30 | Vrije Universiteit Brussel | Variable fragments of immunoglobulins - use for therapeutic or veterinary purposes |
| JP4271735B2 (ja) | 1997-04-15 | 2009-06-03 | メルク アンド カンパニー，インコーポレイティド | 新規のｌｄｌ−レセプター |
| US6329516B1 (en) | 1997-04-28 | 2001-12-11 | Fmc Corporation | Lepidopteran GABA-gated chloride channels |
| US6926898B2 (en) | 2000-04-12 | 2005-08-09 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| EP1395285A4 (en) | 2001-05-17 | 2005-06-01 | Genome Therapeutics Corp | REAGENTS AND METHODS FOR MODULATING DKK-MEDIATED INTERACTIONS |
| JP4303105B2 (ja) | 2001-06-28 | 2009-07-29 | ドマンティス リミテッド | 二重特異性リガンドとその利用 |
| WO2003059934A2 (en) | 2001-12-21 | 2003-07-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| CN1678634A (zh) * | 2002-06-28 | 2005-10-05 | 多曼蒂斯有限公司 | 免疫球蛋白单个变体抗原结合区及其特异性构建体 |
| EP1558645B1 (en) | 2002-11-08 | 2011-07-27 | Ablynx N.V. | Stabilized single domain antibodies in pharmaceutical composition adapted for inhalation |
| US8461155B2 (en) | 2003-09-22 | 2013-06-11 | University Of Connecticut | Sclerostin and the inhibition of WNT signaling and bone formation |
| WO2006040153A2 (en) | 2004-10-13 | 2006-04-20 | Ablynx N.V. | Single domain camelide anti -amyloid beta antibodies and polypeptides comprising the same for the treatment and diagnosis of degenarative neural diseases such as alzheimer's disease |
| AU2006249144B2 (en) | 2005-05-18 | 2011-11-17 | Ablynx Nv | Improved NanobodiesTM against Tumor Necrosis Factor-alpha |
| WO2007027509A2 (en) | 2005-08-31 | 2007-03-08 | Biogen Idec Ma Inc. | Evaluating and treating scleroderma |
| JP2010500876A (ja) | 2006-08-18 | 2010-01-14 | アブリンクス エン．ヴェー． | Ｉｌ−６媒介性シグナル伝達に関連する疾患及び障害の治療のための、ｉｌ−６ｒに指向性を有するアミノ酸配列及びこれを含むポリペプチド |
| US20100113339A1 (en) | 2006-09-08 | 2010-05-06 | Ablynx N. V. | Serum albumin binding proteins with long half-lives |
| JP2010511397A (ja) | 2006-12-05 | 2010-04-15 | アブリンクス エン．ヴェー． | 血清タンパク質と結合可能なペプチド |
| US20110091462A1 (en) | 2008-03-05 | 2011-04-21 | Ablynx N.V. | Novel antigen binding dimer-complexes, methods of making and uses thereof |
| CA2721202A1 (en) | 2008-04-17 | 2009-10-22 | Hilde Adi Pierrette Revets | Peptides capable of binding to serum proteins and compounds, constructs and polypeptides comprising the same |
| US8716243B2 (en) | 2008-05-28 | 2014-05-06 | St. Jude Childen's Research Hospital | Methods of effecting Wnt signaling through Dkk structural analysis |
| CA2777527C (en) | 2009-12-23 | 2020-06-23 | Esbatech, An Alcon Biomedical Research Unit Llc | Method for decreasing immunogenicity |
| EP2531523A1 (en) | 2010-02-05 | 2012-12-12 | Ablynx N.V. | Peptides capable of binding to serum albumin and compounds, constructs and polypeptides comprising the same |
| PH12012501744A1 (en) | 2010-03-03 | 2021-08-09 | Boehringer Ingelheim Int | Biparatopic abeta binding polypeptides |
| KR101899835B1 (ko) * | 2010-03-24 | 2018-09-19 | 제넨테크, 인크. | 항-ｌｒｐ６ 항체 |
| SG185416A1 (en) * | 2010-05-06 | 2012-12-28 | Novartis Ag | Compositions and methods of use for therapeutic low density lipoprotein -related protein 6 (lrp6) antibodies |
| MX2012012927A (es) | 2010-05-06 | 2013-05-01 | Novartis Ag | Composiciones y metodos de uso para anticuerpos multivalentes terapeuticos de proteina relacionada con lipoproteina de baja densidad 6 (lrp6). |
| CN103501799A (zh) * | 2011-01-28 | 2014-01-08 | 莱兰斯坦福初级大学评议会 | Wnt组合物及其使用方法 |
| US9527925B2 (en) | 2011-04-01 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Bispecific binding molecules binding to VEGF and ANG2 |
| US8790650B2 (en) | 2011-04-28 | 2014-07-29 | Vanderbilt University | Methods of using an antibody to inhibit WNT-mediated cardiac remodeling |
| CA3141978A1 (en) | 2011-06-23 | 2012-12-27 | Ablynx Nv | Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains |
| MY167125A (en) | 2011-08-17 | 2018-08-13 | Glaxo Group Ltd | Modified proteins and peptides |
| US8883735B2 (en) | 2011-11-04 | 2014-11-11 | Novartis Ag | Low density lipoprotein-related protein 6 (LRP6)-half life extender constructs |
| SG10201601747XA (en) * | 2012-01-18 | 2016-04-28 | Genentech Inc | Anti-LRP5 Antibodies And Methods Of Use |
| AU2016357460B2 (en) * | 2015-11-18 | 2023-07-27 | Ablynx Nv | Improved serum albumin binders |
| PT3383425T (pt) * | 2015-12-04 | 2020-10-07 | Boehringer Ingelheim Int | Polipéptidos biparatópicos que antagonizam a sinalização wnt em células tumorais |
| US11033636B2 (en) * | 2017-05-31 | 2021-06-15 | Boehringer Ingelheim International Gmbh | Polypeptides antagonizing Wnt signaling in tumor cells |
| US11578129B2 (en) * | 2019-03-29 | 2023-02-14 | Boehringer Ingelheim International Gmbh | LRP5 and PD-1 antagonist anticancer combination therapy |
-
2018
- 2018-05-30 US US15/992,345 patent/US11033636B2/en active Active
- 2018-05-30 MX MX2019014331A patent/MX2019014331A/es unknown
- 2018-05-30 NZ NZ758031A patent/NZ758031A/en unknown
- 2018-05-30 MA MA048760A patent/MA48760A/fr unknown
- 2018-05-30 HU HUE18729376A patent/HUE067691T2/hu unknown
- 2018-05-30 PE PE2019002493A patent/PE20200610A1/es unknown
- 2018-05-30 EA EA201992808A patent/EA201992808A1/ru unknown
- 2018-05-30 AR ARP180101427A patent/AR111840A1/es unknown
- 2018-05-30 UA UAA201911920A patent/UA125761C2/uk unknown
- 2018-05-30 EP EP18729376.6A patent/EP3630816B1/en active Active
- 2018-05-30 CN CN201880033136.9A patent/CN110637030B/zh active Active
- 2018-05-30 JP JP2019565865A patent/JP7216024B2/ja active Active
- 2018-05-30 PL PL18729376.6T patent/PL3630816T3/pl unknown
- 2018-05-30 BR BR112019022729A patent/BR112019022729A2/pt unknown
- 2018-05-30 KR KR1020197033590A patent/KR102717656B1/ko active Active
- 2018-05-30 CA CA3060401A patent/CA3060401A1/en active Pending
- 2018-05-30 AU AU2018276409A patent/AU2018276409B2/en active Active
- 2018-05-30 TW TW107118382A patent/TWI887192B/zh active
- 2018-05-30 WO PCT/EP2018/064295 patent/WO2018220080A1/en not_active Ceased
- 2018-05-30 ES ES18729376T patent/ES2979194T3/es active Active
- 2018-05-30 MY MYPI2019006657A patent/MY200744A/en unknown
-
2019
- 2019-10-08 ZA ZA2019/06610A patent/ZA201906610B/en unknown
- 2019-10-31 CO CONC2019/0012329A patent/CO2019012329A2/es unknown
- 2019-11-20 PH PH12019502602A patent/PH12019502602A1/en unknown
- 2019-11-24 IL IL270854A patent/IL270854B2/en unknown
- 2019-11-25 CL CL2019003419A patent/CL2019003419A1/es unknown
-
2021
- 2021-05-10 US US17/316,042 patent/US12285493B2/en active Active
-
2025
- 2025-03-20 US US19/085,495 patent/US20250345448A1/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7844558B2 (ja) | リンパ球における阻害経路の中和 | |
| JP6779299B2 (ja) | 抗ｐｄ−ｌ１抗体およびその使用 | |
| JP6961897B2 (ja) | 癌治療のためのｔ細胞活性化及び／又はチェックポイント阻害剤を組み合わせたペプチド及びペプチド模倣物 | |
| JP2023153984A (ja) | 腫瘍治療薬及びその応用 | |
| CA3149853A1 (en) | Treatment and prevention of cancer using her3 antigen-binding molecules | |
| JP2019511212A (ja) | ヒトポリオウイルス受容体（ｐｖｒ）に特異的な抗体 | |
| JP2018048139A (ja) | 治療用ペプチド | |
| JP2019506841A5 (enExample) | ||
| JP2018509175A (ja) | 二重特異性四価抗体並びにその製作及び使用方法 | |
| JP2018501197A5 (enExample) | ||
| WO2014012007A4 (en) | Rspo3 binding agents and uses thereof | |
| WO2023174396A1 (zh) | 一种新型免疫调节剂的开发和应用 | |
| US10501549B2 (en) | Methods of inhibiting pathological angiogenesis with doppel-targeting molecules | |
| JP2023544143A5 (enExample) | ||
| JP2021525765A (ja) | スプライシング調節薬の使用方法 | |
| JP2019524706A5 (enExample) | ||
| AU2021378793B2 (en) | Methods and compositions comprising a krasg12c inhibitor and a pd-l1 binding antagonist for treating lung cancer | |
| CN118871467A (zh) | 抗pd-l2抗体 | |
| AU2019235652B2 (en) | Bispecific antibodies to MOSPD2 and T cell- or NK cell-specific molecules | |
| JP2020537690A (ja) | プレクチン１結合抗体およびその使用 | |
| CN114025795B (zh) | 使用靶向her2的双特异性抗原结合构建体治疗胆道癌的方法 | |
| CN118541395A (zh) | 用her3抗原结合分子治疗和预防癌症 | |
| US10202459B2 (en) | Methods of inhibiting pathological angiogenesis with doppel-targeting molecules | |
| ES2946343T3 (es) | Anticuerpos anti-CD137 para combinación con anticuerpos anti-PD-L1 | |
| WO2017175054A1 (en) | Anti-vegfr-1 antibodies and uses thereof |