Single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties
Single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties
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DOI：
10.1080/19420862.2018.1551676
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发表时间：
2019-02-17
期刊：
影响因子：
5.3
通讯作者：
Kamath, Amrita V.
中科院分区：
文献类型：
--
作者：
Ovacik, Ayse Meric;Li, Ji;Kamath, Amrita V.
利用单一宿主细胞生产双特异性抗体是抗体工程领域的一个新进展。我们之前显示了两种新型单细胞变体（v10和v11）和一种传统的双细胞体外组装抗人表皮生长因子受体2/CD 3 T细胞依赖性双特异性（TDB）抗体的体外生物活性和体内小鼠药代动力学（PK）相当。在这里，我们扩展了我们以前的工作，以评估针对FcRH 5的新型TDB的单细胞产生的双特异性变体，FcRH 5是在多发性骨髓瘤（MM）肿瘤细胞上表达的B细胞谱系标志物。先前开发了体外组装的抗FcRH 5/CD 3 TDB抗体作为MM的潜在治疗选择。将用于在单细胞中制造抗FcRH 5/CD 3 TDB的抗体设计（设计v10和v11）与在双细胞方法中体外组装的TDB进行比较，以了解抗体设计和生产的差异是否导致其体外生物活性的任何主要差异，体内小鼠PK和食蟹猴（cynos）中的PK/药效学（PD）或免疫原性。这些单细胞TDB在小鼠和食蟹猴中的结合、体外效力、体外药理学活性和体内PK与体外组装的TDB相当。此外，单细胞和体外组装的TDB在食蟹猴中表现出稳健的PD活性和相当的免疫原性。总体而言，这些研究表明，单细胞产生的和体外组装的抗FcRH 5/CD 3 T细胞依赖性双特异性抗体具有相似的体外和体内性质，并支持进一步开发抗FcRH 5/CD 3 TDB和其他单细胞双特异性抗体的单细胞产生方法。
Bispecific antibody production using single host cells has been a new advancement in the antibody engineering field. We previously showed comparable in vitro biological activity and in vivo mouse pharmacokinetics (PK) for two novel single cell variants (v10 and v11) and one traditional dual cell in vitro-assembled anti-human epidermal growth factor receptor 2/CD3 T-cell dependent bispecific (TDB) antibodies. Here, we extended our previous work to assess single cell-produced bispecific variants of a novel TDB against FcRH5, a B-cell lineage marker expressed on multiple myeloma (MM) tumor cells. An in vitro-assembled anti-FcRH5/CD3 TDB antibody was previously developed as a potential treatment option for MM. Two bispecific antibody variants (designs v10 and v11) for manufacturing anti-FcRH5/CD3 TDB in single cells were compared to in vitro-assembled TDB in a dual-cell process to understand whether differences in antibody design and production led to any major differences in their in vitro biological activity, in vivo mouse PK, and PK/pharmacodynamics (PD) or immunogenicity in cynomolgus monkeys (cynos). The binding, in vitro potencies, in vitro pharmacological activities and in vivo PK in mice and cynos of these single cell TDBs were comparable to those of the in vitro-assembled TDB. In addition, the single cell and in vitro-assembled TDBs exhibited robust PD activity and comparable immunogenicity in cynos. Overall, these studies demonstrate that single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties, and support further development of single-cell production method for anti-FcRH5/CD3 TDBs and other single-cell bispecifics.