尽管在不同B细胞恶性肿瘤的T细胞相关疗法开发方面取得了重大进展，但在难治性疾病环境中仍存在较高医疗需求，该环境常以亚最佳靶标水平为特征。为解决这一问题，我们开发了一个65kDa的多特异抗体结构，称为CLN-978，其亲合力调整以最大程度优化低表达CD19的肿瘤细胞的杀伤效果。CLN-978与B细胞上的CD19具有皮摩尔级的亲和力，并与T细胞上的CD3ε具有纳摩尔级的亲和力。我们还引入了血清白蛋白结合域以延长血清半衰期。在这种设置下，我们在细胞共培养实验、多种小鼠模型和非人灵长类动物中对CLN-978进行了生物物理学特性的表征和报道。通过CLN-978重新定向的人T细胞能够消除表面CD19表达少于300个拷贝的目标细胞。半衰期延长和对CD19的高亲合力导致了非常低剂量CLN-978在小鼠淋巴瘤模型中的显著抗肿瘤活性。在灵长类动物中，我们观察到长时间的血清半衰期，正常B细胞的深层而持续的耗竭，以及卓越的耐受性，特别是当通过皮下途径给予CLN-978时，降低了细胞因子释放。CLN-978值得进一步探索。正在进行的临床1期试验正在研究非霍奇金淋巴瘤患者皮下给予CLN-978的安全性、药代动力学、药效学以及初始治疗潜力。©作者（或其雇主） 2023。在CC BY-NC许可下重新使用。不得商业再利用。发表于BMJ。

Despite significant progress in the development of T cell-engaging therapies for various B-cell malignancies, a high medical need remains for the refractory disease setting, often characterized by suboptimal target levels.To address this issue, we have developed a 65-kDa multispecific antibody construct, CLN-978, with affinities tuned to optimize the killing of low-CD19 expressing tumor cells. CLN-978 bound to CD19 on B cells with picomolar affinity, and to CD3ε on T cells with nanomolar affinity. A serum albumin binding domain was incorporated to extend serum half-life. In this setting, we biophysically characterize and report the activities of CLN-978 in cell co-culture assays, multiple mouse models and non-human primates.Human T cells redirected by CLN-978 could eliminate target cells expressing less than 300 copies of CD19 on their surface. The half-life extension and high affinity for CD19 led to significant antitumor activity in murine lymphoma models at very low doses of CLN-978. In primates, we observed a long serum half-life, deep and sustained depletion of normal B cells, and remarkable tolerability, in particular, reduced cytokine release when CLN-978 was administered subcutaneously.CLN-978 warrants further exploration. An ongoing clinical phase 1 trial is investigating safety, pharmacokinetics, pharmacodynamics, and the initial therapeutic potential of subcutaneously administered CLN-978 in patients with non-Hodgkin's lymphoma.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.