Gautherot E, Bouhou J, Le Doussal J M, Manetti C, Martin M, Rouvier E, Barbet J
IMMUNOTECH SA, Marseille, France.
Cancer. 1997 Dec 15;80(12 Suppl):2618-23. doi: 10.1002/(sici)1097-0142(19971215)80:12+<2618::aid-cncr37>3.3.co;2-p.
One of the main limitations of radioimmunotherapy (RIT) is the secondary toxicity related to the poor therapeutic indices achieved with labeled whole immunoglobulin (Ig)G or F(ab')2 fragments. To overcome this problem, we have developed a two-step targeting method, which we refer to as the Affinity Enhancement System (AES), using a radiolabeled bivalent hapten and a bispecific antibody recognizing the hapten and a target cell antigen. This method has been applied successfully to immunoscintigraphy in carcinoembryonic antigen (CEA)-expressing carcinoma patients and increased tumor to normal tissue uptake ratios have been achieved. The aim of the current study was to evaluate the application of AES to RIT of CEA-expressing solid tumors in an animal model.
Nude mice grafted with LS174T human colorectal carcinoma were treated either with 111 megabecquerels (MBq) of iodine-131 labeled bivalent diethylenetriamine pentaacetic acid (DTPA) hapten 20 hours after pretargeting by anti-CEA x anti-DTPA-indium bispecific antibody or 12 MBq of iodine-131 labeled anti-CEA IgG.
Treatment with the IgG induced only a growth delay of 53 +/- 5 days but all tumors progressed. Treatment with the AES was highly efficient because tumor growth inhibition was achieved over 150 days. Hematologic and overall toxicity of both treatments were equivalent.
The long term tumor regression consecutive to AES RIT represents a very significant improvement over the use of directly labeled IgG. Toxicity consecutive to AES or IgG RIT were similar despite an administered activity nearly ten times higher with the AES. However, given the efficacy of the AES treatment, a lower dose may afford lower toxicity and significant antitumor effect.
放射免疫疗法（RIT）的主要局限性之一是与标记的全免疫球蛋白（Ig）G或F（ab'）2片段所实现的较差治疗指数相关的继发性毒性。为克服这一问题，我们开发了一种两步靶向方法，我们称之为亲和力增强系统（AES），该方法使用放射性标记的二价半抗原和识别半抗原及靶细胞抗原的双特异性抗体。该方法已成功应用于表达癌胚抗原（CEA）的癌症患者的免疫闪烁显像，并实现了肿瘤与正常组织摄取率的提高。本研究的目的是在动物模型中评估AES在表达CEA的实体瘤RIT中的应用。
接种LS174T人结肠直肠癌的裸鼠在通过抗CEA×抗二乙三胺五乙酸（DTPA）-铟双特异性抗体预靶向20小时后，用111兆贝可勒尔（MBq）的碘-131标记的二价DTPA半抗原或12 MBq的碘-131标记的抗CEA IgG进行治疗。
用IgG治疗仅导致53±5天的生长延迟，但所有肿瘤均进展。用AES治疗非常有效，因为在150天以上实现了肿瘤生长抑制。两种治疗的血液学毒性和总体毒性相当。
与直接标记的IgG相比，AES RIT后的长期肿瘤消退代表了非常显著的改善。尽管AES的给药活度几乎高出近10倍，但AES或IgG RIT后的毒性相似。然而，鉴于AES治疗的疗效，较低剂量可能具有较低的毒性和显著的抗肿瘤作用。
