RU2016150377A - Сайт-специфичная конъюгация линкерных лекарственных препаратов с антителами и получаемые в результате adc - Google Patents
Сайт-специфичная конъюгация линкерных лекарственных препаратов с антителами и получаемые в результате adc Download PDFInfo
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- RU2016150377A RU2016150377A RU2016150377A RU2016150377A RU2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A
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- 239000003814 drug Substances 0.000 title claims 8
- 230000021615 conjugation Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 17
- 229940079593 drug Drugs 0.000 claims 6
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims 5
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 235000018417 cysteine Nutrition 0.000 claims 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 206010028980 Neoplasm Diseases 0.000 claims 3
- 239000000611 antibody drug conjugate Substances 0.000 claims 2
- 229940049595 antibody-drug conjugate Drugs 0.000 claims 2
- 239000000427 antigen Substances 0.000 claims 2
- 102000036639 antigens Human genes 0.000 claims 2
- 108091007433 antigens Proteins 0.000 claims 2
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical class COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 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
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 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
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 claims 1
- 210000000170 cell membrane Anatomy 0.000 claims 1
- 210000001072 colon Anatomy 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 239000008176 lyophilized powder Substances 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 claims 1
- 210000003741 urothelium Anatomy 0.000 claims 1
- 206010046766 uterine cancer Diseases 0.000 claims 1
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- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/17—Metallocarboxypeptidases (3.4.17)
- C12Y304/17021—Glutamate carboxypeptidase II (3.4.17.21)
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- A61K31/47—Quinolines; Isoquinolines
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- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
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- C07K2317/515—Complete light chain, i.e. VL + CL
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- C07K2317/55—Fab or Fab'
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- C07K2317/77—Internalization into the cell
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Claims (25)
1. Соединение конъюгат антитело-лекарственный препарат, в котором линкерный лекарственный препарат сайт-специфичным образом конъюгирован с антителом через встроенный цистеин в одной или более позициях указанного антитела, выбранных из 40, 41 и 89 тяжелой цепи (согласно нумерации Kabat); и 40 и 41 легкой цепи (согласно нумерации Kabat).
2. Соединение по п. 1, в котором указанный встроенный цистеин находится в одной или более позициях указанного антитела, выбранных из 40 и 41 тяжелой цепи и 40 и 41 легкой цепи в части Fab указанного антитела.
3. Соединение по п. 1 или 2, дополнительно содержащее встроенный цистеин в позиции 375 в части Fc указанного антитела (согласно нумерации Eu).
4. Соединение по любому из пп. 1-3, в котором указанный линкерный лекарственный препарат содержит производную дуокармицина.
5. Соединение конъюгат антитело-лекарственный препарат, в котором линкерный лекарственный препарат сайт-специфичным образом конъюгирован с антителом или связывающим антиген фрагментом антитела через встроенный цистеин в одной или более позициях указанного антитела, выбранных из 40, 41 и 89 тяжелой цепи (согласно нумерации Kabat); 152, 153, 155, 171, 247, 297, 339, 375 и 376 тяжелой цепи (согласно нумерации Eu); и 40, 41, 165 и 168 легкой цепи (согласно нумерации Kabat), при этом указанный линкерный лекарственный препарат содержит производную дуокармицина.
при этом n составляет 0-3, m представляет среднее DAR от 1 до 6, R1 выбирается из
y равно 1-16, и R2 выбирается из
7. Соединение по п. 6, в котором n составляет 0-1, m представляет среднее DAR от 1,5 до 2, R1 представляет собой
y равно 1-4, и R2 выбирается из
8. Соединение по любому из пп. 1-7 с формулой (II)
9. Соединение по любому из пп. 1-8, в котором указанное антитело связывается с антигеном-мишенью, который экспрессирован в или на клеточной мембране опухолевой клетки, и при этом указанное антитело поглощается клеткой после связывания с указанной целью.
10. Соединение по любому из пп. 1-9, в котором указанное антитело представляет собой антитело против аннексина A1, антитело против CD115, антитело против CD123, антитело против CLL-1, антитело против c-MET, антитело против MUC1, антитело против PSMA, антитело против 5T4 или антитело против TF.
11. Соединение по любому из пп. 1-10, в котором указанное антитело представляет собой моноклональное антитело против PSMA или моноклональное антитело против 5T4.
12. Соединение по п. 11, в котором указанный линкерный лекарственный препарат конъюгирован в позиции 41 вариабельной области тяжелой цепи указанного антитела против PSMA, предпочтительно, при этом тяжелая цепь указанного антитела против PSMA содержит последовательность аминокислот с SEQ ID, NO:2, и легкая цепь указанного антитела против PSMA содержит последовательность аминокислот с SEQ ID NO:5.
13. Соединение по п. 11, в котором указанный линкерный лекарственный препарат конъюгирован в позиции 41 вариабельной области тяжелой цепи указанного антитела против 5T4, предпочтительно, при этом тяжелая цепь указанного антитела против 5T4 содержит последовательность аминокислот с SEQ ID NO:8, и легкая цепь указанного антитела против 5T4 содержит последовательность аминокислот SEQ ID NO:11.
14. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-13 и один или более фармацевтически приемлемых эксципиентов, предпочтительно, в форме лиофилизированного порошка.
15. Соединение по любому из пп. 1-13 или фармацевтическая композиция по п. 14 для применения в качестве медикамента.
16. Соединение по любому из пп. 1-13 или фармацевтическая композиция по п. 14 для применения в лечении человеческих солидных опухолей и гематологических злокачественных образований.
17. Соединение или фармацевтическая композиция по п. 16, при этом человеческие солидные опухоли выбираются из группы, состоящей из рака груди, рака желудка, рака ободочной и прямой кишки, рака уротелия, рака яичников, рака матки, рака легких, мезотелиомы, рака печени, рака поджелудочной железы и рака простаты.
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