대한핵의학회지 (The Korean Journal of Nuclear Medicine)

대한핵의학회 (The Korean Society of Nuclear Medicine)
권호 표지

$^{111}In$-표지 갈락토즈 접합 항체의 체내분포 및 간에서의 대사 : $^{111}In$-표지 항체와의 비교연구

Biodistribution and Hepatic Metabolism of Galactosylated $^{111}In-Antibody-Chelator$ Conjugates: Comparison with $^{111}In-Antibody-Chelator$ Conjugates

  • 곽동석 (경북대학교 의과대학 핵의학과교실) ;
  • 정규식 (경북대학교 수의과대학 수의학과) ;
  • 하정희 (영남대학교 의과대학 약리학교실) ;
  • 안병철 (경북대학교 의과대학 핵의학과교실) ;
  • 이규보 (경북대학교 의과대학 핵의학과교실) ;
  • 백창흠 (미국국립보건원 임상센터 핵의학과) ;
  • 이재태 (경북대학교 의과대학 핵의학과교실)
  • Kwak, Dong-Suk (Department of Nuclear Medicine, Medical School, Veterinary College, Kyungpook National University) ;
  • Jeong, Kyu-Sik (Department of Veterinary Medicine Veterinary College, Kyungpook National University) ;
  • Ha, Jeoung-Hee (Department of Pharmacology, Yeoungnam University Medical School) ;
  • Ahn, Byeong-Cheol (Department of Nuclear Medicine, Medical School, Veterinary College, Kyungpook National University) ;
  • Lee, Kyu-Bo (Department of Nuclear Medicine, Medical School, Veterinary College, Kyungpook National University) ;
  • Paik, Chang-H. (Department of Nuclear Medicine, Clinical Center, National Institutes of Health) ;
  • Lee, Jae-Tae (Department of Nuclear Medicine, Medical School, Veterinary College, Kyungpook National University)
  • 발행 : 2003.12.30
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초록

목적: 종양의 진단과 치료에 널리 이용되고 있는 단클론항체를 수용체에 결합하는 수송체로 이용할 수 있는지에 대한 가능성 여부를 평가하기 위하여, 간의 asialoglycoprotein 수용체에 결합할 수 있는 갈락토즈접합 단클론항체를 $^{111}In$로 표지하여 체내에서의 분포와 간을 중심으로 한 체내대사를 분석하였고, 그 결과를 갈락토즈를 접합하지 않은 $^{111}In$ 표지 항체와 비교하였다. 재료 및 방법: 인체 림프 구성백혈병 세포에 대한 T101 단일클론항체를 cyclic DTPA dianhydrate(DTPA) 나 2-p-isothiocy-anatobenzyl-6-methyl-DTPA(IB4M) 로 접합하고 갈락토즈를 붙인후 $^{111}In$으로 표지하였다. 생쥐와 흰쥐에서 갈락토즈를 접합한 화합물과 접합하지 않은 화합물의 체내분포와 간대사를 비교분석하였다. 결과: $^{111}In$ 표지 T101항체와 갈락토즈 접합체는 투여량의 대부분이 10분 이내에 간에 섭취되었다. DTPA 접합자를 사용한 경우 IB4M 접합자를 사용한 경우보다 간에 오랫동안 저류되어 주사 후 44시간 간 섭취율이 각각 55%와 20% 였다. 이 기간동안의 DTPA화합물의 방사성 대사산물은 24%가 소변으로 17%가 대변으로 배설되어 유사하였으나 IB4M 화합물은 68%가 대변으로 8%가 소변으로 배설되어 배설경로에 차이가 있었다. 1B4M화합물을 주사후 3시간의 담즙과 간 현탁액을 HPLC로 분석한 결과 IgG와 저류시간(Rt)이 같은 첫 절정에 35%,유리 $^{111}In$과 유사한 절정의 Rt에 65%가 관찰되어 대사산물이 빠르게 답즙으로 배출됨을 알 수 있었고, DTPA 화합물 주사후 3시간 대사산물은 90%가 $^{111}In-DTPA$와 유사한 Rt의 절정을 보였다. 그러나 대변의 $^{111}In$ 의 축적량은 낮아 DTPA 접합화합물은 담도를 통한 빠른 배설이 일어나지 않음을 알 수 있었다. 결론: 단일클론항체에 갈락토즈를 접합한 경우보통의 항체에 비하여 간 섭취가 많고, 간에서의 대사가 촉진된다. 이 경우 사용되는 접합자의 선택에 따라서 대사산물의 성분이 달라지고 간에서의 제거도 차이가 있다. 이러한 대사의 차이점은 향후 종양세포나 조직의 탐색에 이용할 방사능 표지 항체의 제조에 응용될 수 있을 것이다.

Purpose: To evaluate the use of monoclonal antibody (MoAb) as a carrier of the receptor-binding ligand the receptor mediated uptake into liver and subsequent metabolism of $^{111}In-labeled$ galactosylated MoAb-chelator conjugates were investigated and compared with those of $^{111}In$ labeled MoAb. Materials and Methods : T101 MoAb, $IgG_2$ against human lymphocytic leukemic cell, conjugated with cyclic DTPA dianhydride (DTPA) or 2-p-isothiocyanatobenzyl-6-methyl-DTPA (1B4M) was galactosylated with 2-imino-2-methoxyethyl-1-thio-${\beta}$-D-galactose and then radiolabeled with $^{111}In$. Biodistribution and metabolism study was peformed with two $^{111}In-conjugates$ in mice and rats. Results: $^{111}In-labeled$ T101 and its galactosylated conjugates were taken to the liver by the time, mostly within 10 min. However DTPA conjugate was retained longer in the liver than the 1B4M conjugate (55% vs 20% of injected dose at 44 hr). During this time, the radiornetabolite of DTPA conjugate was excreted similarly into urine (24%) and feces (17%). The radiometabolite of 1B4M was excreted primarily into feces (68%) rather than urine (8%). Size exclusion HPLC analysis of the bile and supernatant of liver homogenate showed two peaks the first (35%) with the retention time (Rt) identical to IgG and the second (65%) with Rt similar to free $^{111}In$ at 3 hr post-injection for the 1B4M conjugate, indicating that the metabolite is rapidly excreted through the biliary system. in contrast to DTPA conjugate, the small $^{111}In-DTPA-like$ metabolite was the major radioindium component (90%) in the liver homogenate as early as 3 hour post-injection, but the cumulative radioindium activity in feces was only 17% at 44 hour, indicating that the metabolite from DTPA conjugate does not clear readily through the biliary tract. Conclusion: The galactosylation of the MoAb conjugates resulted in higher hepatocyte uptake and enhanced metabolism, compared to those without galactosylation. Metabolism of the MoAb-conjugates is different between compounds radiolabled with different chelators due to different characteristics of radiometabolites generated in the liver.

키워드

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