초록 ▼

국내 최초로 임상적용이 가능한 치료용 방사성치료제 후보물질 확보를 위하여
1. 고비방사능 Lu-177 분리기술 및 Pilot 시스템 개발
• Yb/Lu-177 분리 기초기술, 컬럼 충진물질 개발 및 분리연구
• LC 개념의 Pilot 분리시스템 구성을 통한 nca Lu-177의 생산 및 분리 실증
2. 방사면역치료제로의 적용을 위한 이기능성 킬레이터 개발
• DTPA-NCS 및 Thiol-Maleimide간 결합을 위한 DTPA계 킬레이터 제조
• Lu-177 표지 효율성 평가
3. 방사성동위원

국내 최초로 임상적용이 가능한 치료용 방사성치료제 후보물질 확보를 위하여
1. 고비방사능 Lu-177 분리기술 및 Pilot 시스템 개발
• Yb/Lu-177 분리 기초기술, 컬럼 충진물질 개발 및 분리연구
• LC 개념의 Pilot 분리시스템 구성을 통한 nca Lu-177의 생산 및 분리 실증
2. 방사면역치료제로의 적용을 위한 이기능성 킬레이터 개발
• DTPA-NCS 및 Thiol-Maleimide간 결합을 위한 DTPA계 킬레이터 제조
• Lu-177 표지 효율성 평가
3. 방사성동위원소 표지기술개발
• 선표지 후접합 최적기술 및정제 용이성이 확보된 최적 표지법 개발
• Anti-HER2 표적 단백체의 제조 및 Lu-177 표지 연구
4. Lu-177 표지 방사성의약품 제조를 위한 신기술 개발
• 소마토스타틴 수용체 표적 진단 치료 방사성신물질 개발
• Lu-177 표지 방사성치료제 제조를 위한 Kit 및 자동합성을 위한 기술개발
5. 전표적화 기술개발
• Lu-177 표지 Streptavidin 및 Biotin 유도체 제조 및 Lu-177 표지 및 안정성 평가
6. Lu-177 표지 방사성면역치료제 후보물질 개발
• 질환표적 항체의 Lu-177 표지용 킬레이터 접합 기술 및 Anti-CD20, Anti-ERBB1, Anti-HER2, Anti-CD-44, Anti-KDR 항체 이용 방사면역치료 후보물질 개발
7. 펩타이드수용체 방사성핵종치료(PRRT) 임상 시험을 위한 연구
•독성시험에 관한 자료 확보 및 방사성치료제 임상시험 수행 계획 수립
(출처: 보고서 요약서 3p)

Abstract ▼

Ⅳ. Research Results
1. Development of production technology for highly specific Lu-177 separation technology and its pilot system.
To produce highly specific Lu-177 in the research reactor‘HANARO, a technology related target, absorption material and equipment for the core separation technology

Ⅳ. Research Results
1. Development of production technology for highly specific Lu-177 separation technology and its pilot system.
To produce highly specific Lu-177 in the research reactor‘HANARO, a technology related target, absorption material and equipment for the core separation technology was investigated. Twenty five mCi per 1 mg of Yb target were produced from acquired technology from a present study. Organic and inorganic C-18 column were applied and successful for the separation of Lu-177, and a pilot system was constructed which will lead to its radiochemical purity of 100%.

2. Development on BFCAs for the radiopharmaceuticals on RIT
Considering the bioactive material characteristics, the apporpriate Lu-177 radiolabelled compounds which will be applied to antibody, peptide for the disease targetting purpose were needed. To develop the BFCAs. derivatives of Thiol, isothiocyante(NCS), CysDTPA-NCS-maleimide, (Cyclohexyl)DTPA-NCS, Thiol-DTPA, Maleimide-LysDTPA, Maleimide-miniPEG-DTPA were developed. A series of radioconjugation using devleoped BFCAs were analysed and Lu-177 lagelling was facile enough to label biomaterials such as peptides, small molecules and antibodies under the room temperature.

3. Development of Radioisotope labelling technology
It is very important to come up with a highly efficient radiolabeling technology to develop the new targetting radioactive chemicals. Also it is essential to have the technology related to get high specific radio chemical purity to target the disease in biological system. In present research, a pre-radio-labelling technology followed by biomolecule conjugation was investigated and resulted in a very significant results in highly specific labelling efficacy and highly purified materials as well. The results shows that Lu-177 remains in highly qualified main reacting agents with developed purification methodology from the current investigation. The results found to be a highly affordable labelling technology which will minimize the human errors and radio contamination during the formulation even when it comes to automatic synthesis.

4. Development of new technology for Lu-177 labelling radiopharmaceuticlas.
Present research was focused to devleop the special formulae for Lu-177-DOTA-TATE to treat neuroendocrine tumor and small lung cancer which are highly expressed with somatostatin positive receptor. For the study, biological activities and minimization of radiation exposure during the therapy to treat small lung cancer, especailly on the kidney. As a results, a cassette module, vial kits and automatic synthesizer were developed for the manufacturing the therapeutic radiopharmaceuticals such as Lu-177-DOTA-TATE which would lead to a facile methodology to produce RIT agents.

5. Development of pretargetting technology using Strepatvidin
To develop the materials for the 2- or 3- steps pretargetting techniques, a monomer type of Streptavidin was formulated and it was labelled with Lu-177 resulting in Lu-177-mono-Streptavidin. Antibodies for the proteins, peptides including antibodies were conjugated with Biotin-NCS at the first step and a derivatives of DOTA-Biotin for Lu-177 labelling were synthesized. Then the synthesized DOTABIOTIN were labelled with Lu-177 and its reactivity was examined via a biodegradbility test to prove whether derivatives of Lu-177-DOTA-Biotin would be suitable for the pretargtting agents for RIT.

6. Development of Lu-177 labelled RIT candidates
The radiolagelling technology and bioconjugation technology were established to develop the mothod which can deliver a therapeutic radioisotope, Lu-177. For the study a bifunctional chelating agents were synthesized and its capability as BFCA were evaluated. According to the results, newly synthesized BFCA were excellent in the radio-lablelling and bio-conjugating activity toward monoclonal antibodies like Rituximab, Zevalin, Cetuximab, Trastuzumab with Lu-177 which turned out to be good candidates for RIT.

7. Research on PRRT Clinical Study
We established the labeling technology of the 177Lu-DOTA-TATE, which is known as a targeting agent for a neuroendocrine tumors in general. After we assessed its beneficial and toxic effects for clinical trials, it is subjected for the submission to the KFDA for domestic clinical trials. For the clinical trials, Phase II, non clinical data was acquired through the appropriate animal study using DOTA-TATE, DOTA-TATE-Lu Complex, Lu-177-DOTA-TATE under the GLP approved laboratory for the several tests in nation and oversea at the same time.
(출처: Summary 12p)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 요약서 ... 3
• 요약문 ... 4
• SUMMARY ... 10
• CONTENTS ... 16
• 목차 ... 19
• 제 1 장 연구개발과제의 개요 ... 22
• 제 1 절 연구개발의 목적 ... 22
• 제 2 절 연구개발의 필요성 ... 23
• 제 3 절 연구개발의 내용 및 범위 ... 26
• 제 2 장 국내외 기술개발 현황 ... 28
• 제 1 절 국외 연구개발 동향 및 기술 수준 ... 28
• 제 2 절 국내 연구개발 동향 및 선진국과의 격차 ... 29
• 제 3 장 연구개발 수행 내용 및 결과 ... 30
• 제 1 절 고비방사능 Lu-177 분리기술 및 Pilot 시스템 개발 ... 30
• 1. 서론 ... 30
• 2. 주요연구 수행 내용 ... 32
• 제 2 절 방사면역치료제로의 적용을 위한 이기능성 킬레이터 개발 ... 67
• 1. 서론 ... 67
• 2. 주요연구 수행 내용 ... 68
• 제 3 절 방사성동위원소 표지기술 개발 ... 83
• 1. 서론 ... 83
• 2. 주요연구 내용 ... 83
• 제 4 절 Lu-177 표지 방사성의약품 제조를 위한 신기술 개발 ... 117
• 1. 서론 ... 117
• 2. 주요연구 내용 ... 118
• 제 5 절 전표적화 기술개발 ... 146
• 1. 서론 ... 146
• 2. 주요 연구수행 내용 ... 147
• 제 6 절 Lu-177 표지 방사성면역치료제 후보물질 개발 ... 167
• 1. 서론 ... 167
• 2. 주요연구 수행 내용 ... 171
• 제 7 절 펩타이드수용체 방사성핵종치료(PRRT) 임상 시험을 위한 연구 ... 219
• 1, 서론 ... 219
• 2, 주요연구수행 내용 ... 221
• 제 4 장 목표달성도 및 관련분야에의 기여도 ... 265
• 제 5 장 연구개발결과의 활용계획 ... 269
• 제 6 장 연구개발과정에서 수집한 해외과학기술정보 ... 271
• 제 7 장 참고문헌 ... 274
• 끝페이지 ... 283