Relative Target Affinities of T-Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model
Relative Target Affinities of T-Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model
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DOI：
10.1158/1535-7163.mct-17-0657
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发表时间：
2018-04-01
影响因子：
5.7
通讯作者：
Boswell, C. Andrew
中科院分区：
文献类型：
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作者：
Mandikian, Danielle;Takahashi, Nene;Boswell, C. Andrew
抗HER 2/CD 3是一种T细胞依赖性双特异性抗体（TDB）构建体，通过将肿瘤HER 2与细胞毒性T细胞上的CD 3交联，从而产生功能性溶细胞突触，在表达HER 2的癌细胞中诱导T细胞介导的细胞死亡。TDB设计是一个非常具有挑战性的过程，需要考虑多个参数。尽管治疗性抗体设计策略通常通过争取最高可达到的抗原结合亲和力来驱动，但关于每个TDB臂的亲和力如何影响另一臂的靶向能力以及随之而来的分布和功效知之甚少。据我们所知，尚未发表使用临床前模型的分布研究，其中TDB的T细胞靶向臂与T细胞主动结合。我们采用放射化学、侵入性生物分布和非侵入性单光子发射断层扫描（SPECT）成像相结合的方法来测量TDB在T细胞上表达人CD 3 β的转基因小鼠中的分布和catalyptase。使用CD 3亲和力变体，我们评估了CD 3亲和力对短期药代动力学、组织分布和细胞摄取的影响。我们的实验方法确定了（i）CD 3靶向正常组织，（ii）HER 2靶向表达HER 2的肿瘤，和（iii）相对HER 2/CD 3亲和力的相对作用，所有这些都是TDB分布的关键驱动因素。我们观察到CD 3亲和力和分布到富含T细胞的组织之间存在很强的相关性，较高的CD 3亲和力降低了全身暴露，并将TDB分布从肿瘤转移到含T细胞的组织。这些观察结果对用于癌症免疫治疗的双特异性抗体的临床翻译具有重要意义。(C)2018年AACR。
Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive bio-distribution, and noninvasive single-photon emission tomo-graphic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3 epsilon expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. (C) 2018 AACR.