JP2020509010A5 - - Google Patents

Info

Publication number

JP2020509010A5

JP2020509010A5 JP2019546364A JP2019546364A JP2020509010A5 JP 2020509010 A5 JP2020509010 A5 JP 2020509010A5 JP 2019546364 A JP2019546364 A JP 2019546364A JP 2019546364 A JP2019546364 A JP 2019546364A JP 2020509010 A5 JP2020509010 A5 JP 2020509010A5

Authority

JP

Japan

Prior art keywords

antibody

fusion protein

cysteine

drug

occupied

Prior art date

2018-02-28

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

• Espacenet
• Global Dossier
• Discuss

• 108020001507 fusion proteins Proteins 0.000 claims description 44
• 102000037865 fusion proteins Human genes 0.000 claims description 44
• 235000018417 cysteine Nutrition 0.000 claims description 36
• XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 30
• 229940079593 drug Drugs 0.000 claims description 21
• 239000003814 drug Substances 0.000 claims description 21
• 238000004519 manufacturing process Methods 0.000 claims description 19
• 239000003638 chemical reducing agent Substances 0.000 claims description 14
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 8
• 239000004472 Lysine Substances 0.000 claims description 8
• 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 238000012258 culturing Methods 0.000 claims description 6
• 150000001945 cysteines Chemical group 0.000 claims description 6
• VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical group SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 5
• 229930182480 glucuronide Natural products 0.000 claims description 5
• 210000004027 cell Anatomy 0.000 claims description 4
• PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 claims description 3
• 230000015572 biosynthetic process Effects 0.000 claims description 3
• 210000004899 c-terminal region Anatomy 0.000 claims description 3
• 230000001268 conjugating effect Effects 0.000 claims description 3
• 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 3
• DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims description 3
• MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 2
• IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 2
• 239000011230 binding agent Substances 0.000 claims description 2
• 150000001875 compounds Chemical class 0.000 claims description 2
• 239000000833 heterodimer Substances 0.000 claims description 2
• 239000000611 antibody drug conjugate Substances 0.000 claims 15
• 229940049595 antibody-drug conjugate Drugs 0.000 claims 15
• 238000000034 method Methods 0.000 claims 3
• 239000003795 chemical substances by application Substances 0.000 claims 2
• POBZYODNVHQLFG-ZRBKHQLFSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[methyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-phenylpentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C POBZYODNVHQLFG-ZRBKHQLFSA-N 0.000 claims 1
• 230000021615 conjugation Effects 0.000 claims 1
• 239000000243 solution Substances 0.000 description 3
• 239000002552 dosage form Substances 0.000 description 2
• 238000002347 injection Methods 0.000 description 2
• 239000007924 injection Substances 0.000 description 2
• AJQHISHNPUSHEE-YIURLQAVSA-O CC[C@H](C)[C@@H](C(N(C)[C@H](C[C@H](c1nc(C(N[C@H](C[C@H](C)C(O)=O)Cc2ccccc2)=O)c[s]1)OC(C)=O)C(C)C)=O)NC([C@@H]1[N+](C)(Cc(cc2)cc(NC(CCNC([C@H](CN)N(C(C=C3)=O)C3=O)=O)=O)c2O[C@@H]([C@@H]([C@H]([C@@H]2O)O)O)O[C@@H]2C(O)=O)CCCC1)=O Chemical compound CC[C@H](C)[C@@H](C(N(C)[C@H](C[C@H](c1nc(C(N[C@H](C[C@H](C)C(O)=O)Cc2ccccc2)=O)c[s]1)OC(C)=O)C(C)C)=O)NC([C@@H]1[N+](C)(Cc(cc2)cc(NC(CCNC([C@H](CN)N(C(C=C3)=O)C3=O)=O)=O)c2O[C@@H]([C@@H]([C@H]([C@@H]2O)O)O)O[C@@H]2C(O)=O)CCCC1)=O AJQHISHNPUSHEE-YIURLQAVSA-O 0.000 description 1
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
• 239000008351 acetate buffer Substances 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 239000007864 aqueous solution Substances 0.000 description 1
• 239000000872 buffer Substances 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 239000002270 dispersing agent Substances 0.000 description 1
• 239000012153 distilled water Substances 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
• 230000004927 fusion Effects 0.000 description 1
• 239000012669 liquid formulation Substances 0.000 description 1
• 239000000203 mixture Substances 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 239000000546 pharmaceutical excipient Substances 0.000 description 1
• 235000018102 proteins Nutrition 0.000 description 1
• 108090000623 proteins and genes Proteins 0.000 description 1
• 102000004169 proteins and genes Human genes 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• 239000002904 solvent Substances 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1