초록 ▼

Ⅳ. 연구개발결과
· SA0406 (11B1)에 대한 선도물질 최적화 단계를 통해 확보한 항체들에 대해 In vitro binding affinity분석 및 효능 평가를 통해 SA2449항체를 선별함. SA2449는 SA0406(11B1)와 비교할 때 in vitro binding affinity가 동등이상이며 in vitro co-culture system에서 동등이상의 효능을 나타내는 것을 확인함. 이 항체의 경우 mouse와 monkey에 cross-reactivity를 보이는 것을 확인함 (2020년 국내 특허 출원)<

Ⅳ. 연구개발결과
· SA0406 (11B1)에 대한 선도물질 최적화 단계를 통해 확보한 항체들에 대해 In vitro binding affinity분석 및 효능 평가를 통해 SA2449항체를 선별함. SA2449는 SA0406(11B1)와 비교할 때 in vitro binding affinity가 동등이상이며 in vitro co-culture system에서 동등이상의 효능을 나타내는 것을 확인함. 이 항체의 경우 mouse와 monkey에 cross-reactivity를 보이는 것을 확인함 (2020년 국내 특허 출원)
· SA2449의 경우 간암 세포주 유래 동물 모델에서 항암 효능을 나타내는 것을 확인하였고 폐암 세포주 유래 동물 모델 (Syngeneic model)에서 면역항암 효능을 나타내는 것을 확인함. 또한 PK 분석 결과 복강내 투여인 경우 반감기 (T_1/2)가 male은 7.2일, female은 5.5일로 확인함. 단회 및 2주 DRF 독성 분석 결과 임상 이상 소견은 없었음.
· CMG 타깃에 대한 검증을 위해 in vitro 및 in vivo에서 분석한 결과 Oncogenic potential을 보이면서 면역 타깃의 potential을 가지는 것을 확인함.
· 타깃 단백질인 CMG의 binding partner를 IP & LC-MS/MS로 확인한 결과 CMG-L로 확인하였고 두 단백질은 CMG의 C-term region에 결합하는 것을 확인함. 따라서 백업항체로 개발 중인 C-term region항체들을 처리하면 두 단백질 결합이 억제되는 것을 확인함.
· 백업 항체는 C-term region에 대한 항체 스크리닝으로 진행하였고 In vitro binding affinity 및 효능을 in vitro & in vivo model에서 분석한 결과 4종 이상의 항체가 효능을 나타내는 것을 확인함. 그 중 가장 효능이 좋은 항체는 SA2613으로 SA0406 항체의 최적화 후 확보한 SA2449보다 훨씬 높은 효능을 나타내는 것을 확인함. 이 항체에 대해 Affinity maturation을 진행하였고 도출된 항체들 중 30종 항체를 선별하여 SA2613과 동등이상의 항체를 선별 중임. In vitro co-culture를 통해 3종의 항체가 동등이상의 효능을 보이는 것을 확인함. 그 종 1종의 항체가 상대적으로 높은 효능을 보이는 것을 확인함.

(출처 : 요약문 5p)

Abstract ▼

Ⅱ. Objectives
Development of novel immunotherapeutic anti-cancer antibody targeting CMG as a pre-clinical candidate for the treatment of non-small cell lung cancer (NSCLC).
· Functional analysis of novel immune-related protein CMG and the development of anti-CMG therapeutic antibody candidate

Ⅱ. Objectives
Development of novel immunotherapeutic anti-cancer antibody targeting CMG as a pre-clinical candidate for the treatment of non-small cell lung cancer (NSCLC).
· Functional analysis of novel immune-related protein CMG and the development of anti-CMG therapeutic antibody candidate via lead optimization process.
· Biomarker development and validation
· Generation of new back-up anti-CMG antibodies.

Ⅲ. Research Summary
· SA2449 antibody was selected through in vitro binding affinity analysis and efficacy evaluation for antibodies obtained through the lead optimization for SA0406 (11B1).
It was confirmed that SA2449 has an in vitro binding affinity equal to or greater than that of SA0406 (11B1) and exhibits an efficacy equal to or greater in an in vitro co-culture system. It was confirmed that this antibody shows cross-reactivity in mouse and monkey (Korean patent application in 2020)
· In the case of SA2449, we confirmed anti-cancer efficacy in liver cancer cell line-derived xenograft model and immunotherapeutic efficacy in lung caner-derived syngeneic mouse model. In addition, in the case of intraperitoneal administration, we investigated that the half-life (T1/2) was 7.2 days for males and 5.5 days for females through PK analysis. There was no clinical abnormality in the single- and two-week DRF toxicity analysis.
· We confirmed that the CMG target has the potential of an immune target and oncogenic potential through in vitro and in vivo assay.
· As a result of analyzing the binding partner of the target protein CMG through IP & LC-MS/MS, CMG-L was identified, and it was confirmed that the two proteins bind to the C-term region of CMG. Therefore, we demonstrated that the binding of both proteins is inhibited when C-term region antibodies are treated in co-culture with lung cancer cell lines.
· The backup antibody was processed by antibody screening for the C-term region. In vitro binding affinity and efficacy were analyzed in an in vitro & in vivo model, and it was confirmed that four or more antibodies showed efficacy.

Among them, the most effective antibody was SA2613, which was found to show much higher efficacy than SA2449 obtained after lead optimization of the SA0406 antibody. We performed the affinity maturation for SA2613, and selected 30 antibodies. These antibodies have an in vitro binding affinity equal to or greater than SA2613. It was confirmed through the in vitro co-culture that the three types of antibodies showed equal or higher efficacy.
· Immunoanticancer drugs targeting CMGs such as SA2449 and SA2613 are anticancer drugs that are being developed as lung cancer treatments based on predicting and responding to treatment responses after discovering and verifying a new target called CMG. In particular, it can be applied to a group of patients who do not have PD-L1 expression and express CMG, so it can be presented as a new treatment to patients who do not currently have treatment.
· We are also developing the predictive biomarkers for CMG target therapeutic antibody. In the future, based on the established SOP, it is easy to select a patient group in clinical trials and maximize the efficacy, so it is highly likely to succeed.
· A preclinical trial is planned in 2021, and for this purpose, a study for cell line production will be conducted from December 2020. The next step from the production of cell lines will be carried out by Samsung Biologics, and the contract for the cell line production been completed.
· It is planned to analyze the efficacy of combination with existing drugs, And we're planning to analyze the efficacy for this antibody various carcinomas.
· Starting in the second half of 2020, we are planning a partnership meeting for full-scale technology transfer and there were a number of companies that showed interest when introduced to BIO Europe in 2019.
· We are confirming the efficacy of overcoming target anti-cancer or chemotherapy resistance. It is intended to confirm the possibility of being applied to the CMG (+) patient group while being PD-L1(-) and to present it as a new treatment to this patient group. In addition, it is planning to conduct an IND submission in 2022 by rapidly conducting research with anti-cancer drugs based on predicting treatment response biomarkers.

(source : SUMMARY 7p)

목차 Contents

• 표지 ... 1
• 제 출 문 ... 2
• 보고서 요약서 ... 3
• 요 약 문 ... 4
• SUMMARY ... 7
• CONTENTS ... 9
• 목차 ... 10
• 제1장 연구개발과제의 개요 ... 11
• 제1절 연구개발의 목적 ... 11
• 제2절 연구개발의 필요성 ... 11
• 제3절 연구개발의 범위 ... 16
• 제2장 국내외 기술개발 현황 ... 18
• 제1절 시장규모와 성장세 (Size and Growth) ... 18
• 제2절 경쟁약물 (Competition) ... 21
• 제3장 연구개발수행 내용 및 결과 ... 22
• 제1절 선도물질 최적화 ... 22
• 제2절 타겟 검증 (in vitro/in vivo system에서 CMG 기능 규명) ... 32
• 제3절 In vitro 항체 항암제 효능 평가 ... 43
• 제4절 In vivo 항체 항암제 효능 평가 ... 51
• 제5절 작용 기전 (MOA) 및 바이오마커 분석 ... 65
• 제6절 생체 내 특성 분석 ... 74
• 제7절 물리/이화학적 특성 분석 ... 78
• 제8절 세포주 구축 ... 84
• 제9절 백업 항체 항암제 스크리닝 ... 86
• 제10절 PD-1 저항성에 대한 개선 효과 가능성 검증 ... 96
• 제10절 지식재산권 (특허) 실적 ... 101
• 제4장 목표달성도 및 관련분야에의 기여도 ... 102
• 제1절 최종목표 ... 102
• 제2절 목표달성도 ... 102
• 제3절 관련 분야에의 기여도 ... 107
• 제5장 연구개발결과의 활용계획 ... 108
• 제1절 추가 연구의 필요성 ... 108
• 제2절 기업화 추진방안 ... 108
• 제6장 연구개발과정에서 수집한 해외과학기술정보 ... 110
• 제7장 연구시설·장비 현황 ... 112
• 제8장 참고문헌 ... 113
• 끝페이지 ... 113