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首页> 外文期刊>British Journal of Cancer >Xenogeneic monoclonal antibodies in the management of cancer: control of their in vivo immunogenicity and induction of specific unresponsiveness using an antibody-drug immunoconjugate
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Xenogeneic monoclonal antibodies in the management of cancer: control of their in vivo immunogenicity and induction of specific unresponsiveness using an antibody-drug immunoconjugate

机译：异种单克隆抗体在癌症的治疗中：使用抗体-药物免疫偶联物控制其体内免疫原性和诱导特异性无反应性

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A bispecific mouse monoclonal antibody (mAb) that recognises carcinoembryonic antigen (CEA) with one binding site and vinblastine (VLB) with the other was used, and its in vivo immunosuppressive effect specific for anti-mouse immunoglobulin (Ig) was studied. The antibody was incubated with VLB at a molar ratio (MR) of 1:1, and administered i.v. to rabbits. Control animals received either the MAb alone, or the MAb with VLB covalently linked (MR 1:1), or the parental anti-CEA with equimolar amount of VLB. Seven days later, the rabbit anti-mouse Ig primary response was measured, and found to be almost 55% reduced in the animals that received the VLB 'loaded' MAb. In vivo kinetics and stability experiments revealed that the T1/2 of the MAb was 68 +/- 5 h, whereas free VLB disappeared within minutes. It was concluded that as soon as the drug dissociates from the antibody's binding site, it is rapidly removed. This problem was overcome by subcutaneously implanting osmotic mini-pumps containing VLB. The pumps released the drug at a constant rate for a period greater than 1 week, saturating the antibody's binding site. Under these conditions rabbits developed 80% less anti-mouse Ig antibodies when the bispecific antibody was administered (compared with the parental anti-CEA). The immunosuppression observed was specific for the mouse Ig, under conditions compatible with the full clinical therapeutic potential of the MAb. In conclusion, these experiments show, that it is possible to develop hybrid antibodies that can act as a 'lethal bait' to any specific lymphocyte in vivo, thus preventing undesirable responses against the xenogeneic MAb.
机译：使用了识别具有一个结合位点的癌胚抗原（CEA）和具有另一个结合位点的长春碱（VLB）的双特异性小鼠单克隆抗体（mAb），并且研究了其对抗小鼠免疫球蛋白（Ig）特有的体内免疫抑制作用。将抗体与VLB以1∶1的摩尔比（MR）温育，并静脉内施用。给兔子对照动物接受单独的MAb或具有共价连接的VLB的MAb（MR 1：1），或接受等摩尔量的VLB的亲本抗CEA。 7天后，测量了兔抗小鼠Ig的主要反应，发现接受VLB“负载” MAb的动物减少了近55％。体内动力学和稳定性实验表明，MAb的T1 / 2为68 +/- 5 h，而游离的VLB在数分钟内消失。结论是，一旦药物从抗体的结合位点解离，就会迅速将其除去。通过皮下植入含有VLB的渗透微型泵克服了这个问题。泵以恒定速率释放药物超过1周，使抗体的结合位点饱和。在这些条件下，施用双特异性抗体（与亲本抗CEA相比），兔子产生的抗小鼠Ig抗体减少了80％。在与MAb的全部临床治疗潜能兼容的条件下，观察到的免疫抑制对小鼠Ig具有特异性。总之，这些实验表明，有可能开发出可在体内充当针对任何特定淋巴细胞的“致命诱饵”的杂交抗体，从而防止针对异种MAb的不良反应。

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