Behr T M, Memtsoudis S, Sharkey R M, Blumenthal R D, Dunn R M, Gratz S, Wieland E, Nebendahl K, Schmidberger H, Goldenberg D M, Becker W
Department of Nuclear Medicine, Georg-August-University, Göttingen, Germany.
Int J Cancer. 1998 Aug 31;77(5):787-95. doi: 10.1002/(sici)1097-0215(19980831)77:5<787::aid-ijc19>3.0.co;2-z.
Whereas bivalent fragments have been widely used for radio-immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of (131)I-labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose-limiting organ toxicity and anti-tumor efficacy. The maximum tolerated doses (MTDs) and dose-limiting organ toxicities of the (131)I-labeled anti-CEA antibody MN-14 [IgG, F(ab')2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D-lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 (131)I-labeled immunoconjugates [IgG, F(ab')2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 microCi for IgG, 1,200 microCi for F(ab')2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab')2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti-tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments.
虽然二价片段已广泛用于放射免疫治疗，但关于单价缀合物在体内治疗性能的系统性研究尚未发表。因此，我们研究的目的是确定与二价缀合物相比，¹³¹I标记的Fab的治疗性能，并分析影响剂量限制性器官毒性和抗肿瘤疗效的因素。在携带人结肠癌皮下异种移植瘤的裸鼠中，测定了¹³¹I标记的抗癌胚抗原（CEA）抗体MN-14[IgG、F(ab')₂和Fab]的最大耐受剂量（MTD）和剂量限制性器官毒性。对小鼠进行有或无骨髓移植（BMT）、用D-赖氨酸抑制抗体片段的肾脏摄取或两者联合处理。监测毒性和肿瘤生长情况。根据生物分布数据计算辐射剂量学。对于所有三种¹³¹I标记的免疫缀合物[IgG、F(ab')₂和Fab]，红骨髓是唯一的剂量限制性器官；IgG的MTD为260μCi，F(ab')₂为1200μCi，Fab为3mCi，分别对应血液剂量17Gy、9Gy和4Gy。然而，与IgG相比，Fab的初始剂量率高10倍，与F(ab')₂相比高3倍。所有三种免疫缀合物的MTD通过BMT增加了约30%。由于肾脏剂量低于10Gy，未观察到肾毒性迹象。尽管肿瘤吸收剂量较低，但在等毒性给药时，Fab片段在控制肿瘤生长方面比相应的二价片段或IgG更有效，这可能是由于肿瘤内剂量率较高。我们的数据表明，与IgG相比，抗体片段抗肿瘤有效性的提高以及在相对较低的红骨髓剂量下更高的骨髓毒性，很可能是由于抗体片段观察到的较高初始剂量率。
