Johnson D A, Barton R L, Fix D V, Scott W L, Gutowski M C
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Cancer Res. 1991 Oct 15;51(20):5774-6.
Human anti-mouse antibody has been a nearly consistent result of human clinical trials utilizing murine antibodies. It is generally anticipated that the problem of human anti-mouse antibody will be reduced as genetically engineered, more human ("humanized") antibodies become available. It is not clear, however, what effect chemical modification of such "humanized" antibodies will have on their immunogenicity. The present studies utilize a mouse antibody and rat host model to explore aspects of this question. Rats injected with unmodified mouse monoclonal antibodies failed to mount anti-mouse immune responses, presumably due to their phylogenetic relatedness. In contrast, rats injected with a Vinca immunoconjugate mounted strong anticonjugate antibody responses that were directed primarily against the linker portion of the conjugate. The in vivo serum pharmacokinetics of 125I-labeled antibody and conjugates were evaluated in rats with existing anticonjugate antibody. The peak serum level attained was inversely correlated with the level of reactivity of the anticonjugate antibody with the injected compound. This model provides a potentially useful tool for exploration of the immunogenicity of drug, toxin, or radionuclide monoclonal antibody conjugates.
在利用鼠源抗体进行的人类临床试验中，人抗鼠抗体几乎一直是个结果。一般预计，随着基因工程改造的、更具人源化的抗体问世，人抗鼠抗体问题将会减少。然而，尚不清楚这种“人源化”抗体的化学修饰会对其免疫原性产生何种影响。本研究利用小鼠抗体和大鼠宿主模型来探究该问题的各个方面。注射未修饰小鼠单克隆抗体的大鼠未能产生抗鼠免疫反应，推测是由于它们的系统发育相关性。相比之下，注射长春花免疫缀合物的大鼠产生了强烈的抗缀合物抗体反应，主要针对缀合物的连接部分。在已存在抗缀合物抗体的大鼠中评估了125I标记抗体和缀合物的体内血清药代动力学。达到的血清峰值水平与抗缀合物抗体与注射化合物的反应性水平呈负相关。该模型为探索药物、毒素或放射性核素单克隆抗体缀合物的免疫原性提供了一个潜在有用的工具。
