Bispecific monoclonal antibodies can bind two protein targets simultaneously and enable therapeutic modalities inaccessible by traditional mAbs. Bispecific formats containing a heterodimeric Fc region are of particular interest, as a heterodimeric Fc empowers both bispecificity and altered valencies while retaining the developability and druggability of a monoclonal antibody. We present a robust heterodimeric Fc platform, called the XmAb® bispecific platform, engineered for efficient development of bispecific antibodies and Fc fusions of multiple formats. First, we engineer a purification solution for proteins containing a heterodimeric Fc using engineered isoelectric point differences in the Fc region that enable straightforward purification of the heterodimeric species. Then, we combine this purification solution with a novel set of Fc substitutions capable of achieving heterodimer yields over 95% with little change in thermostability. Next, we illustrate the flexibility of our heterodimeric Fc with a case study in which a wide range of tumor-associated antigen × CD3 bispecifics are generated, differing in choice of tumor antigen, affinities for both tumor antigen and CD3, and tumor antigen valency. Finally, we present manufacturing data reinforcing the robustness of the heterodimeric Fc platform at scale.

中文翻译：

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一个强大的异二聚体 Fc 平台，用于高效开发多种形式的双特异性抗体

双特异性单克隆抗体可以同时结合两个蛋白质靶标，实现传统 mAb 无法实现的治疗方式。包含异二聚 Fc 区的双特异性形式是特别令人感兴趣的，因为异二聚 Fc 赋予双特异性和改变的价态，同时保留单克隆抗体的可开发性和成药性。我们提供了一个强大的异二聚体 Fc 平台，称为 XmAb® 双特异性平台，专为高效开发双特异性抗体和多种形式的 Fc 融合而设计。首先，我们使用 Fc 区域中的工程等电点差异设计了一种用于含有异二聚体 Fc 的蛋白质的纯化解决方案，从而能够直接纯化异二聚体物种。然后，我们将此纯化解决方案与一组新的 Fc 取代相结合，能够实现超过 95% 的异二聚体产率，而热稳定性几乎没有变化。接下来，我们通过一个案例研究来说明我们的异二聚体 Fc 的灵活性，其中产生了广泛的肿瘤相关抗原 × CD3 双特异性，不同的肿瘤抗原选择、对肿瘤抗原和 CD3 的亲和力以及肿瘤抗原价。最后，我们提供了大规模增强异二聚体 Fc 平台稳健性的制造数据。对肿瘤抗原和 CD3 的亲和力以及肿瘤抗原效价。最后，我们提供了大规模增强异二聚体 Fc 平台稳健性的制造数据。对肿瘤抗原和 CD3 的亲和力以及肿瘤抗原效价。最后，我们提供了大规模增强异二聚体 Fc 平台稳健性的制造数据。