Friedrich Stuart W, Lin Stephany C, Stoll Brian R, Baxter Laurence T, Munn Lance L, Jain Rakesh K
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Neoplasia. 2002 Sep-Oct;4(5):449-63. doi: 10.1038/sj.neo.7900260.
The failure of the cellular immune response to stop solid tumor growth has been the subject of much research. Although the mechanisms for tumor evasion of immune response are poorly understood, one viable explanation is that tumor-killing lymphocytes cannot reach the tumor cells in sufficient quantity to keep the tumor in check. Recently, the use of bifunctional antibodies (BFAs) has been proposed as a way to direct immune cells to the tumor: one arm of the antibody is specific for a known tumor-associated antigen and the other for a lymphocyte marker such as CD3. Injecting this BFA should presumably result in cross-linking of lymphocytes (either endogenous or adoptively transferred) with tumor cells, thereby enhancing therapy. Results from such an approach, however, are often disappointing--frequently there is no benefit gained by using the BFA. We have analyzed the retargeting of endogenous effector cells by BFA using a physiologically based whole-body pharmacokinetic model that accounts for interactions between all relevant species in the various organs and tumor. Our results suggest that the design of the BFA is critical and the binding constants of the antigen and lymphocyte binding epitopes need to be optimized for successful therapy.
细胞免疫反应无法阻止实体瘤生长一直是众多研究的主题。尽管肿瘤逃避免疫反应的机制尚不清楚，但一种可行的解释是，杀伤肿瘤的淋巴细胞无法足量抵达肿瘤细胞以控制肿瘤。最近，有人提出使用双功能抗体（BFA）作为将免疫细胞导向肿瘤的一种方法：抗体的一个臂对已知的肿瘤相关抗原有特异性，另一个臂对淋巴细胞标志物如CD3有特异性。注射这种BFA大概会使淋巴细胞（内源性的或过继转移的）与肿瘤细胞交联，从而增强治疗效果。然而，这种方法的结果往往令人失望——使用BFA常常没有益处。我们使用基于生理学的全身药代动力学模型分析了BFA对内源性效应细胞的重定向作用，该模型考虑了各个器官和肿瘤中所有相关物质之间的相互作用。我们的结果表明，BFA的设计至关重要，抗原和淋巴细胞结合表位的结合常数需要优化才能实现成功治疗。
