인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
Current antibody-drug conjugates (ADCs) face limitations due to a lack of tumor-selective targets, inefficient internalization, and challenges in reaching tumors in challenging sites, ultimately limiting their therapeutic efficacy. We developed and characterized V66-exatecan, a novel ADC composed of V66, a humanized antibody with high affinity for extracellular DNA (exDNA), conjugated to exatecan via a cleavable linker. This ADC employs a dual-targeting mechanism based on exDNA and ENT2 transporter expression to enhance nuclear drug delivery and tumor specificity. This study evaluates its anti-tumor activity, mechanism of action, ability to treat challenging tumors, and safety profile. To validate tumor selectivity, V66 or a control antibody were conjugated to a fluorescent tag and injected intravenously into tumor-bearing mice; biodistribution analysis demonstrated selective accumulation in tumors and nuclear localization within tumor cells. V66 was then conjugated to exatecan via a cleavable linker. In vitro assays across diverse cancer cell lines assessed cytotoxicity, DNA damage response (DDR) activation, and TOP1 degradation. In vivo efficacy was evaluated in xenograft models of triple-negative breast cancer (TNBC) and BRCA1/2-deficient tumors, including intracranial medulloblastoma. These models were used to assess tumor growth inhibition, survival benefit, and blood-brain barrier (BBB) permeability. Toxicity was assessed through a dose-escalation study, with analysis of hematologic parameters, histopathology of major organs, and liver and kidney function tests (ALT, AST, BUN, total protein) following short- and long-term treatment. V66-exatecan demonstrated potent anti-tumor activity in multiple cancer cell lines but not on healthy mouse primary fibroblasts, with EC50 values in the low nanomolar range. It induced robust DDR signaling, TOP1 degradation, and bystander killing effects. BRCA1/2-deficient models exhibited enhanced penetration and sensitivity, with up to 17-fold lower EC50 compared to BRCA-proficient controls. In vivo, V66-exatecan significantly inhibited tumor growth and extended survival in both TNBC and BRCA-mutant CNS tumors, including complete regressions and prolonged median survival in BRCA2-deficient models. Toxicology studies revealed no significant hematologic, renal, hepatic, or bone marrow toxicity, even at high or repeated doses. V66-exatecan represents a next-generation of ADCs that overcomes key limitations of traditional platforms by exploiting exDNA-driven tumor selectivity and ENT2-mediated nuclear delivery. It demonstrates broad therapeutic efficacy and a favorable safety profile, supporting its potential for treating DDR-deficient and hard-to-reach tumors.
인공지능 문자 인식 모델을 통해 추출된 텍스트로, 일부 오타나 오류가 포함될 수 있으나 지속적으로 개선 중입니다.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
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