CA2762877A1 - Polyal drug conjugates comprising variable rate-releasing linkers - Google Patents
Polyal drug conjugates comprising variable rate-releasing linkers Download PDFInfo
- Publication number
- CA2762877A1 CA2762877A1 CA2762877A CA2762877A CA2762877A1 CA 2762877 A1 CA2762877 A1 CA 2762877A1 CA 2762877 A CA2762877 A CA 2762877A CA 2762877 A CA2762877 A CA 2762877A CA 2762877 A1 CA2762877 A1 CA 2762877A1
- Authority
- CA
- Canada
- Prior art keywords
- conjugate
- phf
- polyal
- drug
- gly
- 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.)
- Abandoned
Links
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- 229940079593 drug Drugs 0.000 title claims abstract description 133
- 238000000034 method Methods 0.000 claims abstract description 50
- 229940127093 camptothecin Drugs 0.000 claims description 83
- 125000005647 linker group Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 51
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 48
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 47
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 45
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 43
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000004429 atom Chemical group 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 201000011510 cancer Diseases 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
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- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229930182556 Polyacetal Natural products 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229920001855 polyketal Polymers 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 239000000872 buffer Substances 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical group CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 8
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- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
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- CEVCTNCUIVEQOY-UHFFFAOYSA-N Fumagillol Natural products O1C(CC=C(C)C)C1(C)C1C(OC)C(O)CCC21CO2 CEVCTNCUIVEQOY-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CEVCTNCUIVEQOY-STXHBLNNSA-N fumagillol Chemical compound C([C@@H](O)[C@H](C1[C@]2(C)[C@H](O2)CC=C(C)C)OC)C[C@@]21CO2 CEVCTNCUIVEQOY-STXHBLNNSA-N 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 2
- 239000000562 conjugate Substances 0.000 description 129
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 17
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- 239000000203 mixture Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 150000003443 succinic acid derivatives Chemical class 0.000 description 5
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
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- 210000004027 cell Anatomy 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
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- 238000012377 drug delivery Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
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- 238000000338 in vitro Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 230000004962 physiological condition Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
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Classifications
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Landscapes
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Applications Claiming Priority (3)
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| US18192609P | 2009-05-28 | 2009-05-28 | |
| US61/181,926 | 2009-05-28 | ||
| PCT/US2010/036413 WO2010138719A1 (en) | 2009-05-28 | 2010-05-27 | Polyal drug conjugates comprising variable rate-releasing linkers |
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| CN101990441A (zh) * | 2007-11-28 | 2011-03-23 | 默萨那治疗学股份有限公司 | 生物相容的生物可降解的烟曲霉素类似物轭合物 |
| CA2794307A1 (en) * | 2010-03-26 | 2011-09-29 | Mersana Therapeutics, Inc. | Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof |
| US9233163B2 (en) * | 2010-12-28 | 2016-01-12 | The Children's Hospital Of Philadelphia | Hydrolytically releasable prodrugs for sustained release nanoparticle formulations |
| KR102087854B1 (ko) * | 2011-06-10 | 2020-03-12 | 메르사나 테라퓨틱스, 인코포레이티드 | 단백질-중합체-약물 접합체 |
| US8815226B2 (en) | 2011-06-10 | 2014-08-26 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| EP2773373B1 (en) | 2011-11-01 | 2018-08-22 | Bionomics, Inc. | Methods of blocking cancer stem cell growth |
| US20130189218A1 (en) * | 2011-12-23 | 2013-07-25 | Mersana Therapeutics, Inc. | Pharmaceutical formulations for fumagillin derivative-phf conjugates |
| EP2928504B1 (en) * | 2012-12-10 | 2019-02-20 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| WO2014093379A1 (en) * | 2012-12-10 | 2014-06-19 | Mersana Therapeutics, Inc. | Auristatin compounds and conjugates thereof |
| EP2931316B1 (en) | 2012-12-12 | 2019-02-20 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
| EP3590922A1 (en) | 2013-03-15 | 2020-01-08 | Zymeworks Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| BR112016007410B1 (pt) | 2013-10-04 | 2022-07-19 | Prolynx Llc | Conjugados de sn-38 de liberação lenta, formulações farmacêuticas, métodos de preparo do referido conjugado e usos relacionados |
| EA032231B1 (ru) * | 2013-10-11 | 2019-04-30 | Мерсана Терапьютикс, Инк. | Конъюгаты белок-полимер-лекарственное средство |
| IL245009B (en) | 2013-10-11 | 2022-08-01 | Asana Biosciences Llc | Protein-polymer-drug conjugates |
| ES2916722T3 (es) | 2013-12-27 | 2022-07-05 | Zymeworks Inc | Sistemas de enlace que contienen sulfonamida para conjugados de fármacos |
| CA2960899C (en) | 2014-09-17 | 2021-08-17 | Zymeworks Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| AU2015339012B2 (en) | 2014-10-31 | 2020-11-05 | Abbvie Biotherapeutics Inc. | Anti-CS1 antibodies and antibody drug conjugates |
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- 2010-05-27 CN CN2010800236442A patent/CN102448469A/zh active Pending
- 2010-05-27 CA CA2762877A patent/CA2762877A1/en not_active Abandoned
- 2010-05-27 US US12/789,047 patent/US8524214B2/en not_active Expired - Fee Related
- 2010-05-27 AU AU2010254013A patent/AU2010254013A1/en not_active Abandoned
- 2010-05-27 JP JP2012513256A patent/JP2012528240A/ja active Pending
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| AU2010254013A1 (en) | 2011-11-24 |
| AR078510A1 (es) | 2011-11-16 |
| KR20120057588A (ko) | 2012-06-05 |
| TW201102089A (en) | 2011-01-16 |
| IL216325A0 (en) | 2012-01-31 |
| EP2435053A1 (en) | 2012-04-04 |
| US20100305149A1 (en) | 2010-12-02 |
| EP2435053A4 (en) | 2016-03-16 |
| US8524214B2 (en) | 2013-09-03 |
| JP2012528240A (ja) | 2012-11-12 |
| WO2010138719A1 (en) | 2010-12-02 |
| EP2435053B1 (en) | 2018-11-14 |
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