WO2014208987A1 - 안정성이 개선된 항체-약물 결합체 및 이의 용도 - Google Patents
안정성이 개선된 항체-약물 결합체 및 이의 용도 Download PDFInfo
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- WO2014208987A1 WO2014208987A1 PCT/KR2014/005589 KR2014005589W WO2014208987A1 WO 2014208987 A1 WO2014208987 A1 WO 2014208987A1 KR 2014005589 W KR2014005589 W KR 2014005589W WO 2014208987 A1 WO2014208987 A1 WO 2014208987A1
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- LXEMXIOOAGRSRJ-PQUPALFMSA-N CCC(C)[C@@H](C(C)CC(N(CCC1)C1/C(/[C@@H](C)C(/N=C(\Cc1ccccc1)/C(O)=O)=O)=[O]\C)=O)N(C)C([C@H](C(C)C)NC([C@H](C(C)C)N(C)C(CCCCC=O)=O)=O)=O Chemical compound CCC(C)[C@@H](C(C)CC(N(CCC1)C1/C(/[C@@H](C)C(/N=C(\Cc1ccccc1)/C(O)=O)=O)=[O]\C)=O)N(C)C([C@H](C(C)C)NC([C@H](C(C)C)N(C)C(CCCCC=O)=O)=O)=O LXEMXIOOAGRSRJ-PQUPALFMSA-N 0.000 description 1
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Abstract
Description
항체-약물 결합체 | ||
결합 종류 | 결합 조건 | 결합체 명칭 (Trastuzumab, MMAF 사용 시) |
Cys 결합 | Thiomab(HC A114C), Mal-C6-MMAF | Thiomab-MMAF |
Thiol 결합 | Mal-C6-MMAF | T-C-MMAF |
Lys 결합 | SMCC 링커, SH-C6-MMAF | T-K-MMAF |
Amine 결합 | ALD-C6-MMAF (약산성 pH 조건) | T-N-MMAF |
No. of bound drug | Mass (Da) | Relative intensity(%) | Da |
0 | 145179.5 | 1.8 | - |
1 | 146005.3 | 10.7 | 825.8 |
2 | 146833.2 | 21.2 | 827.9 |
3 | 147661.1 | 25.4 | 827.9 |
4 | 148488.9 | 21.0 | 827.8 |
5 | 149317.0 | 12.5 | 828.1 |
6 | 150145.5 | 5.0 | 828.5 |
7 | 150964.2 | 2.3 | 818.7 |
DAR | 3.219 | ||
DAR = Sum(Intensity(%) x No. of Drug / 100)Drug moiety mass : 828 Da |
트립신 단편(Trypsin fragment) | Ratio | |
중쇄-N말단 | EVQLVESGGGLVQPGGSLR (서열번호 1) | 46% |
경쇄-N말단 | DIQMTQSPSSLSASVGDR (서열번호 2) | 29% |
중쇄-CH2 | THTCPPCPAPELLGGPSVFLFPPKPKDTLMISR (서열번호 3) | 17% |
그외 | - | 8% |
시료 | 항원 결합력 | ||
Test 1 (10-10 M) | Test 2 (10-10 M) | 평균 (10-10 M) | |
트라스투주맙 | 1.3 | 2.2 | 1.8 |
T-N-MMAF (DAR 1.6) | 1.2 | 0.9 | 1.1 |
T-N-MMAF (DAR 3.2) | 1.1 | 0.7 | 0.9 |
Cell line | Cytotoxicity (IC50 (pM)) | ||
T-N-MMAF(DAR 3.2) | T-C-MMAF(DAR 3.6) | T-K-MMAF(DAR 3.9) | |
HCC1954 | 40 | 22 | 45 |
SKOV-3 | 104 | 59 | N.D. |
JIMT1 | 253 | 98 | 727 |
BT474 | 116 | 49 | 77 |
시료 | 단일클론항체의 상대적 함량(보관 7일, %) | 결합체의 상대적 함량(보관 7일, %) | DAR의 상대적 함량(보관 7일, %) |
Trastuzumab | 90.0 | - | - |
T-N-MMAF | 89.3 | 90.5 | 101.4 |
T-C-MMAF | 49.2 | 32.3 | 65.6 |
Thiomab-MMAF | 69.9 | 59.5 | 85.1 |
랫트에 ADC를 2.5mg/kg 용량으로 투여한 다음, 측정한 PK 파라미터 | ||||||
Treatment (n=5, each)2-compartment modeling | Total Ab | Conjugated Ab | ||||
AUC(hr*㎍/ml) | T1/2(hr) | Cmax(㎍/ml) | AUC(hr*㎍/ml) | T1/2(hr) | Cmax(㎍/ml) | |
Trastzumab | 6964.9 | 115.7 | 128.1 | - | - | - |
T-N-MMAF | 6795.7 | 122.1 | 111.2 | 6813.2 | 118.3 | 112.4 |
T-C-MMAF | 5933.5 | 111.6 | 94.3 | 4315.4 | 84.6 | 93.7 |
T-K-MMAF | 4324.3 | 65.1 | 157.5 | 3781.7 | 53.2 | 190.0 |
T-N-MMAE의 DAR별 화학종 분포도 및 평균 DAR | |||
No. of drug | Mass (Da) | Relative content (%) | Delta mass |
D0 | N/D | N/D | |
D1 | 146061.05 | 6.3 | |
D2 | 146863.77 | 14.3 | 802.72 |
D3 | 147672.80 | 23.3 | 809.03 |
D4 | 148484.33 | 24.2 | 811.53 |
D5 | 149297.30 | 16.5 | 812.97 |
D6 | 150112.25 | 8.6 | 814.95 |
D7 | 150922.84 | 6.8 | 810.59 |
DAR | 3.83 |
μg/ml | % | DAR | % | |
Day 0 | 364.8 | 100% | 3.17 | 100% |
Day 3 | 346.9 | 95% | 3.33 | 105% |
Day 7 | 294.8 | 81% | 3.28 | 103% |
T-N-MMAE 의 rat PK 파라미터. | ||||
Group | AUC(hr*㎍/ml) | Conjugate/Total ratio | half-life (hr) | Conjugate/Total ratio |
trastuzumab | 5868.83 | 169.6 | ||
T-N-MMAF (T) | 6688.95 | 191.8 | ||
T-N-MMAF (C) | 6871.71 | 103% | 203.3 | 106% |
T-N-MMAE (T) | 5639.24 | 173.9 | ||
T-N-MMAE (C) | 5690.96 | 101% | 163.7 | 94% |
* 시험간 비교를 위해 trastuzumab과 T-N-MMAF를 포함하였다. |
Her2 발현 종양 세포주에 대한 T-N-MMAE의 세포 독성 | |||
IC50[nM] | |||
#1 | #2 | Average | |
HCC1954 | 0.39 | 0.26 | 0.33 |
SKOV-3 | 3.04 | 2.62 | 2.83 |
JIMT1 | 4.00 | 3.51 | 3.76 |
BT474 | 0.56 | 0.70 | 0.63 |
No. of bound drug | Mass (Da) | Relative content (%) | Delta mass(Da) |
D0 | 145208.6 | 3.1 | |
D1 | 146034.9 | 14 | 826.3 |
D2 | 146863.3 | 24.4 | 828.4 |
D3 | 147692 | 26.4 | 828.7 |
D4 | 148520.7 | 18.2 | 828.7 |
D5 | 149349.7 | 9.3 | 829 |
D6 | 150177.5 | 4.7 | 827.8 |
DAR | 2.90 |
Cell line | IC50(pM) |
Karpas-299 | 32.2 |
L-540 | 37.1 |
No. of bound drugs | Mass (Da) | Relative content (%) | Delta mass (Da) |
D0 | 147001.5 | 3.3 | |
D1 | 147830.8 | 10.8 | 829.3 |
D2 | 148657.9 | 18.6 | 827.1 |
D3 | 149486.6 | 22.7 | 828.7 |
D4 | 150315.4 | 20.1 | 828.8 |
D5 | 151144.7 | 13.7 | 829.3 |
D6 | 151973.5 | 7 | 828.8 |
D7 | 152803 | 3.7 | 829.5 |
DAR | 3.329 |
IC50[nM] | ||
OPM-2 | L-N-MMAF DAR 2.5 | 52.9 |
L-N-MMAF DAR 3.3 | 41.9 |
SK-MEL-2 | IC50(nM) |
G-N-MMAF DAR 2.2 | 5.47 |
G-N-MMAF DAR 3.4 | 3.36 |
Claims (21)
- 항체의 중쇄 또는 경쇄의 N-말단 아미노산 잔기에 세포독성 약물(cytotoxic drug)이 결합된, 항체-약물 결합체(antibody-drug conjugate, ADC).
- 제1항에 있어서,상기 항체의 중쇄 또는 경쇄의 N-말단의 α-아민기에 세포독성 약물이 결합된 것인, 항체-약물 결합체.
- 제2항에 있어서,α-아민기와 반응하여 가교할 수 있는, 세포독성 약물의 반응기를 통하여 세포독성 약물이 항체에 연결된 형태인 것인, 항체-약물 결합체.
- 제3항에 있어서,상기 α-아민기와 반응하여 가교할 수 있는 반응기는 아이소티오시아네이트(isothiocyanate), 아이소시아네이트(isocyanates), 아실 아자이드(acyl azide), NHS 에스터(NHS ester), 설포닐 클로라이드(sulfonyl chloride), 알데하이드(aldehyde), 글리옥살(glyoxal), 에폭사이드(epoxide), 옥시레인(oxirane), 칼보네이트(carbonate), 아릴 할라이드(aryl halide), 이미도에스터(imidoester), 카보이미드(carbodiimide), 안하이드라이드(anhydride) 및 플루오로페닐 에스터(fluorophenyl ester)로 이루어진 군에서 선택된 것인, 항체-약물 결합체.
- 제1항에 있어서,상기 항체는 전장 항체, 또는 항원 결합 도메인을 포함하는 항체 단편 형태인 것인, 항체-약물 결합체.
- 제5항에 있어서,상기 항체는 IgG, scFv, Fv, Fab, Fab' 및 F(ab')2로 이루어진 군으로부터 선택된 형태를 가지는 것인, 항체-약물 결합체.
- 제1항에 있어서,상기 세포독성 약물은 마이크로튜불린(microtubulin) 구조 형성 억제제, 유사분열(meiosis) 억제제, RNA 중합효소 억제제, 토포아이소머라아제(topoisomerase) 억제제, DNA 인터컬레이터(DNA intercalators), DNA 알킬레이터(DNA akylator), 리보솜 억제제, 방사선 동위원소 및 독소로 이루어진 군으로부터 선택되는 것인, 항체-약물 결합체.
- 제7항에 있어서,상기 세포독성 약물은 메이탄시노이드(maytansinoid), 오리스타틴(auristatin), 돌라스타틴(dolastatin), 튜브라이신(tubulysin), 칼리케아미신(calicheamicin), 피롤로벤조디아제피네스(pyrrolobenzodiazepines), 독소루비신(doxorubicin), 듀오카마이신(duocamycin), 카보플라틴(파라플라틴)[Carboplatin(paraplatin)], 시스플라틴(cisplatin), 시클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 니드란(nidran), 질소머스타드(메클로에타민 염산염)[nitrogen mustar(mechlorethamine HCL)], 블레오마이신(bleomycin), 미토마이신 C(mitomycin C), 시타라빈(cytarabine), 플루로우라실(flurouracil), 젬시타빈(gemcitabine), 트리메트렉세이트(trimetrexate), 메토크렉세이트(methotrexate), 에토포시드(etoposide), 빈블라스틴(vinblastine),비노렐빈(vinorelbine), 알림타(alimta), 알트레타민(altretamine), 프로카바진(procarbazine), 탁솔(taxol), 탁소텔(taxotere), 토포테칸(topotecan), 이리노테칸(irinotecan), 트리코테센(trichothecene), CC1065, 알파-아마니틴(alpha-amanitin) 균체 외독소 및 식물독소로 이루어진 군으로부터 선택된 것인, 항체-약물 결합체.
- 제8항에 있어서,상기 오리스타틴은 모노메틸 오리스타틴 E(Monomethyl auristatin E) 또는 모노메틸 오리스타틴 F(Monomethyl auristatin F)인 것인, 항체-약물 결합체.
- 제1항에 있어서,상기 항체는 암세포 표면 항원에 특이적으로 결합하는 것인, 항체-약물 결합체.
- 제10항에 있어서,상기 암세포 표면 항원은 CD19, CD20, CD30, CD33, CD37, CD22, CD56, CD70, CD74, CD138, Muc-16, mesothelin, HER2, HER3, GPNMB(glycoprotein NMB), IGF-1R, BCMA(B cell maturation antigen), PSMA(prostate-specific membrane antigen), EpCAM(Epithelial cell adhesion molecule) 및 EGFR(epidermal growth factor receptor)로 이루어진 군에서 선택된 것인, 항체-약물 결합체.
- 제1항에 있어서,상기 항체는 항-HER2 항체, 항-CD30 항체, 항-CD56 항체 및 항-GPNMB(glycoprotein NMB) 항체로 이루어진 군으로부터 선택된 것인, 항체-약물 결합체.
- 제12항에 있어서,상기 항체는 트라스투주맙(Trastuzumab), 로보투주맙(Lorvotuzumab), 브렌투시맙(Brentuximab) 및 글렘바투무맙(Glembatumumab)으로 이루어진 군에서 선택된 것인, 항체-약물 결합체.
- 항체의 중쇄 또는 경쇄의 N-말단 아미노산 잔기에 면역억제제가 결합된, 항체-약물 결합체(antibody-drug conjugate, ADC).
- α-아민기와 반응하여 가교할 수 있는 반응기를 포함하는 세포독성 약물 또는 면역억제제와 항체를 반응시켜, 항체의 중쇄 또는 경쇄의 N-말단의 α-아민기에 세포독성 약물 또는 면역억제제를 연결시키는 단계를 포함하는, 제1항 내지 제14항 중 어느 한 항의 항체-약물 결합체의 제조방법.
- 제15항에 있어서,상기 제조방법은 추가로 결합체를 형성하지 않은 항체, 및 세포독성 약물 또는 면역 억제제를 포함하는 반응 산물로부터 항체-약물 결합체를 분리하는 단계를 포함하는 것인, 제조방법.
- 제15항에 있어서,상기 α-아민기와 반응하여 가교할 수 있는 반응기는 아이소티오시아네이트(isothiocyanate), 아이소시아네이트(isocyanates), 아실 아자이드(acyl azide), NHS 에스터(NHS ester), 설포닐 클로라이드(sulfonyl chloride), 알데하이드(aldehyde), 글리옥살(glyoxal), 에폭사이드(epoxide), 옥시레인(oxirane), 칼보네이트(carbonate), 아릴 할라이드(aryl halide), 이미도에스터(imidoester), 카보이미드(carbodiimide), 안하이드라이드(anhydride) 및 플루오로페닐 에스터(fluorophenyl ester)로 이루어진 군에서 선택된 것인 제조방법.
- 제1항 내지 제13항 중 어느 한 항의 항체-약물 결합체를 포함하는, 암 치료용 약학적 조성물.
- 제14항의 항체-약물 결합체를 포함하는, 자가면역질환의 치료용 약학적 조성물.
- 제1항 내지 제13항 중 어느 한 항의 항체-약물 결합체를 암 의심 개체에 투여하는 단계를 포함하는, 암의 치료 방법.
- 제14항의 항체-약물 결합체를 자가면역질환 의심 개체에 투여하는 단계를 포함하는, 자가면역질환의 치료 방법.
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AU2014299561A AU2014299561B2 (en) | 2013-06-24 | 2014-06-24 | Antibody-drug conjugate having improved stability and use thereof |
BR112015032200A BR112015032200A2 (pt) | 2013-06-24 | 2014-06-24 | conjugado anticorpo-droga com estabilidade melhorada, método de preparação, composição farmacêutica e uso do mesmo |
CA2916202A CA2916202C (en) | 2013-06-24 | 2014-06-24 | Antibody-drug conjugate having improved stability and use thereof |
CN201480035895.0A CN105377307B (zh) | 2013-06-24 | 2014-06-24 | 具有改进的稳定性的抗体-药物缀合物及其用途 |
RU2016102116A RU2670748C9 (ru) | 2013-06-24 | 2014-06-24 | Конъюгаты антител с лекарственными агентами, обладающие улучшенной стабильностью, и их применение |
JP2016523642A JP6208864B2 (ja) | 2013-06-24 | 2014-06-24 | 安定性が改善された抗体−薬物結合体およびこれの用途 |
EP14817162.2A EP3015116B1 (en) | 2013-06-24 | 2014-06-24 | Antibody-drug conjugate having improved stability and use thereof |
US14/898,126 US10071170B2 (en) | 2013-06-24 | 2014-06-24 | Antibody-drug conjugate having improved stability and use thereof |
US16/059,761 US20180360986A1 (en) | 2013-06-24 | 2018-08-09 | Antibody-drug conjugate having improved stability and use thereof |
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US16/059,761 Division US20180360986A1 (en) | 2013-06-24 | 2018-08-09 | Antibody-drug conjugate having improved stability and use thereof |
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CN (2) | CN110251683A (ko) |
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US20160136300A1 (en) | 2016-05-19 |
EP3015116A4 (en) | 2017-03-08 |
BR112015032200A2 (pt) | 2017-11-21 |
US20180360986A1 (en) | 2018-12-20 |
JP2016523900A (ja) | 2016-08-12 |
CN105377307A (zh) | 2016-03-02 |
EP3015116A1 (en) | 2016-05-04 |
CN110251683A (zh) | 2019-09-20 |
CA2916202C (en) | 2019-07-02 |
AU2014299561B2 (en) | 2017-06-08 |
US10071170B2 (en) | 2018-09-11 |
KR101641206B1 (ko) | 2016-07-22 |
AU2014299561A1 (en) | 2016-01-21 |
CN105377307B (zh) | 2019-09-24 |
RU2670748C9 (ru) | 2018-12-13 |
KR20150000843A (ko) | 2015-01-05 |
RU2016102116A (ru) | 2017-07-28 |
JP6208864B2 (ja) | 2017-10-04 |
CA2916202A1 (en) | 2014-12-31 |
EP3015116B1 (en) | 2020-02-26 |
RU2670748C2 (ru) | 2018-10-25 |
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