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Kafe 바로가기주관연구기관 | 에이비온(주) |
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연구책임자 | 송경 |
참여연구자 | 신영기 , 박상호 , 이영일 , 윤선주 , 최성현 , 박현숙 , 김득애 , 이윤수 , 곽은혜 , 최지현 , 안장현 , 장은진 , 이주호 , 박하연 , 곽지원 , 오준식 , 박정은 , 이희정 , 정성훈 , 김남아 , 임대곤 , 홍성열 , 장수정 , 이세형 , 허진영 , 정성훈 , 홍성렬 |
보고서유형 | 1단계보고서 |
발행국가 | 대한민국 |
언어 | 한국어 |
발행년월 | 2017-11 |
주관부처 | (범부처사업) NTIS |
등록번호 | TRKO202000031183 |
DB 구축일자 | 2020-12-12 |
키워드 | 다발성경화증.인터페론 베타.비임상연구.바이오베터.단백질 치료제.Multiple sclerosis.interferon beta.Preclinical study.biobetter.protein therapeutics. |
초기 배양 최종산물의 titer (25ug/mL) 기준, 최종 62g/mL까지 titer를 향상, 당초 연구목표 (40ug/mL)를 성공적으로 충족시킴. 초기 정제 순도 (90%) 기준, 최종 95%이상으로, 당초 연구목표를 성공적으로 충족시킴. 당초 pI 7.4이상 basic variant 및 RP-HPLC peak 상대함량기준 90% purity에서 최종 공정개발을 통해 얻은 단백질은 pI 7.4이하의 acidic variant, HCP>100ppm, RP-HPLC시 monomer 함량 99%이상을 만족하였으므로 최종 목표를 달
초기 배양 최종산물의 titer (25ug/mL) 기준, 최종 62g/mL까지 titer를 향상, 당초 연구목표 (40ug/mL)를 성공적으로 충족시킴. 초기 정제 순도 (90%) 기준, 최종 95%이상으로, 당초 연구목표를 성공적으로 충족시킴. 당초 pI 7.4이상 basic variant 및 RP-HPLC peak 상대함량기준 90% purity에서 최종 공정개발을 통해 얻은 단백질은 pI 7.4이하의 acidic variant, HCP>100ppm, RP-HPLC시 monomer 함량 99%이상을 만족하였으므로 최종 목표를 달성하였음. 효능실험결과 대조물질과 비교하여 ABN101의 마우스 수용체에 대한 affinity가 낮음에도 불구하고 동등의 효능을 나타낸 결과를 보았을 때, 대조물질 대비 생체 내 안정성 등에서 ABN101의 우위성을 확인할 수 있었음. ABN101 Rat PK 실험결과 Rebif(sc) 혹은 Avonex(im) 대비 AUC 2배 혹은 반감기 1.5배 이상 증가의 목표에 대해 Rebif 대비 반감기 약 4배 증가로 통계적 유의성을 확인, 당초 연구목표를 성공적으로 충족함. ABN101 Monkey PK 실험결과 Rebif(sc) 혹은 Avonex(im) 대비 AUC 2배 혹은 반감기 1.5배 이상 증가의 목표에 대해 피하에서 AUC가 두 약물 대비 약 3∼5배 이상 증가로 통계적 유의성을 확인, 당초 연구목표를 성공적으로 충족함.
(출처 : 보고서 요약서 3p)
Ⅲ. Study contents & Results
1) Process optimization
- Culture process optimization: Based on the initial culture final product of titer 25 ug / mL, final titer was improved up to 62 g / mL, which successfully meets the original study goal of 40 ug / mL. In order to maximize efficiency, Abi
Ⅲ. Study contents & Results
1) Process optimization
- Culture process optimization: Based on the initial culture final product of titer 25 ug / mL, final titer was improved up to 62 g / mL, which successfully meets the original study goal of 40 ug / mL. In order to maximize efficiency, Abion and Binex independently performed the experiments. Abion achieved the final goal of 40 ug / mL by feed selection. Additionally, critical process parameters were confirmed by DOE (culture temperature 34 ℃, pH 7.0, DO 30%, 8 days fed-batch), and titer was up to more than 60ug/mL by process optimization. Binex achieved the final goal through optimization of DOE (culture temperature 34 ℃-> 32 ℃), pH 7.0, DO 50%, fed-batch 42 ug / ml as the outcome. Fed-batch conditions of incubation temperature of 34 ° C, pH 7.0, DO 30%, and 8 days by Abion was established as the final culture conditions for non-clinical trial study.
- Purification process optimization: Satisfied original goal of refining purity of 90% to greater than 95%. To maximize work efficiency, Abion and Binex shared mutual results and performed experiments to establish a final purity of more than 95%. As the basic variant of pI greater than 7.4 and RP-HPLC peak 90% purity based on relative content, the protein obtained from the final process development satisfied the final goal since the acidic variant of pI 7.4 or less, HCP> 100ppm, and the monomer content was greater than 99% in RP-HPLC.
2) Formulation studies
- Pharmaceutical profiling: Compared to Rebif®, successfully built carbiferon-based database. Based on the confirmation of structure-based thermal stability verification using μDSC, thermal stability data was obtained by basic buffer and six PH conditions. Furthermore, secondary structural stability was evaluated using ATR FT-IR and spectroscopic methods and the comparison result of relative alpha helix contents was verified. Physical stability and viscosity results were obtained by shear stress using mVROC.
-Excipient screening: Discovered trehalose which replaced Mannitol and completed patent application by screening of the carbohydrate which replace the Rebif formulated Mannitol. Coagulation inhibition and structural stabilization by trehalose and arginine HCl studies were completed, which completed the development of the formulation with higher stability than the Rebif formulation.
-Formulation optimization: Completed drafting of 8 final candidates and patent application since the optimized formulation was equal or greater than control / Rebif.
-Accelerated storage stability: Storage stability test of 8 final formulation candidates was performed according to ICH guidelines. During the 3 months, it was confirmed that the monomer was greater than 90% during all formulations refrigerated, and all of the protein aggregation reactions were negative in the refrigerated samples.
3) Comparative effectiveness evaluation between carbiferon and reference materials
As a result of the efficacy study, superiority of ABN101 in vivo stability was confirmed in comparison with the control substance. ABN101 showed equivalent efficacy compared to the control substance even though the affinity of ABN101 to the mouse receptor was low.
4) PK/PD Analysis
-Rat PK: As a result of ABN101 Rat PK data, the final goal of 2x AUC compared to Rebif(sc) or Avonex(im), or 1.5x half-life, the half-life of ABN 101 was increased approximately 4x which confirmed statistical significance and satisfied the initial study goal. The AUC through SC administration, ABN101 increased about 3~5x compared to Rebif and Avonex, which confirmed statistical significance. The AUC through IM administration, ABN101 increased about 5x compared to Rebif and Avonex, which confirmed statistical significance. ABN101 was confirmed statistically superior in the Rat PK compared to the reference substance-Rebif and Avoenx, so data was obtained of the prolonged administration period of ABN101 compared to the reference substance for patients’ convenience.
-Monkey PK/PD: As a result of ABN101 Monkey PK data, the final goal of 2x AUC compared to Rebif(sc) or Avonex(im), or 1.5x half-life, the half-life of ABN 101 was increased approximately 3~5x greater which confirmed statistical significance and satisfied the initial study goal. IV administration prolonged systemic exposure possibility confirmed by the body disappearing rate which was 2 to 4x lower than Rebif and Avonex. The AUC through SC administration, compared to Avonex, ABN101 increased about 3~5x, which confirmed statistical significance. The increased systemic exposure showed in IV result was also confirmed by statistical significance. The AUC through IV administration, ABN101 increased about 5 times compared to Rebif and Avonex, which confirmed statistical significance. The AUC through IM administration, ABN101 increased about 2~3 times compared to Rebif and Avonex, which confirmed statistical significance.ABN101 was confirmed statistically superior in the Monkey PK compared to the reference substance-Rebif and Avoenx, so data was obtained of the prolonged administration period of ABN101 compared to the reference substance for patients’ convenience.
(출처 : SUMMARY 6p)
과제명(ProjectTitle) : | - |
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연구책임자(Manager) : | - |
과제기간(DetailSeriesProject) : | - |
총연구비 (DetailSeriesProject) : | - |
키워드(keyword) : | - |
과제수행기간(LeadAgency) : | - |
연구목표(Goal) : | - |
연구내용(Abstract) : | - |
기대효과(Effect) : | - |
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