Genmab, Utrecht, The Netherlands.
Biologics Research, Janssen Research and Development, LLC., Spring House, PA, USA.
Sci Rep. 2017 May 30;7(1):2476. doi: 10.1038/s41598-017-02823-9.
Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab-arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual-targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre-clinical evaluation in immuno-competent rodents.
利用肿瘤特异性抗体的治疗概念通常在免疫缺陷小鼠的临床前异种移植模型中建立。然而，更复杂的治疗范例需要使用免疫活性小鼠，以更准确地捕捉正在利用的相关生物学。这些模型需要使用（替代）鼠或大鼠抗体来实现与鼠效应分子的最佳相互作用。免疫原性进一步降低，允许进行更长时间的治疗。我们最近描述了控制 Fab 臂交换（cFAE）作为一种易于使用的方法，用于生成治疗性人 IgG1 双特异性抗体（bsAb）。为了促进免疫活性小鼠中双靶向概念的研究，我们现在应用并优化了我们的方法来生成鼠 bsAb。我们表明，匹配点突变的优化组合可有效地生成研究的所有亚类（鼠 IgG1、IgG2a 和 IgG2b；大鼠 IgG1、IgG2a、IgG2b 和 IgG2c）的鼠 bsAb。这些突变不会对相应亚类的固有效应功能或药代动力学特性产生不利影响。因此，cFAE 可用于有效地生成用于免疫活性啮齿动物临床前评估的（替代）鼠或大鼠 bsAb。
