Research and Development, Pieris Pharmaceuticals GmbH, Freising, Germany.
In Vivo Operations, Oncotest GmbH, Freiburg, Germany.
Clin Cancer Res. 2019 Oct 1;25(19):5878-5889. doi: 10.1158/1078-0432.CCR-18-3654. Epub 2019 May 28.
4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.
PRS-343 was generated by the genetic fusion of 4-1BB-specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of assays and humanized mouse models. The safety was assessed using human cell assays and a toxicity study in cynomolgus monkeys.
PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB-expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.
PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule..
4-1BB（CD137）是一种关键的共刺激免疫受体，也是癌症治疗的有前途的靶点。为了克服当前 4-1BB 靶向抗体的局限性，我们开发了 PRS-343，一种 4-1BB/HER2 双特异性分子。PRS-343 的设计目的是通过肿瘤局部的、HER2 依赖性的 4-1BB 聚集和激活，促进 T 细胞的共刺激。
PRS-343 通过将 4-1BB 特异性 Anticalin 蛋白与具有工程 IgG4 同种型的曲妥珠单抗变体进行基因融合而产生。使用一系列测定和人源化小鼠模型对其活性进行了表征。通过人细胞测定和食蟹猴的毒性研究评估了其安全性。
PRS-343 以高亲和力靶向 4-1BB 和 HER2，并同时结合这两个靶点。当在表达 HER2 的癌细胞存在下孵育时，表达 4-1BB 的 T 细胞被 PRS-343 有效共刺激，这表现为促炎细胞因子（IL2、GM-CSF、TNFα 和 IFNγ）的产量增加。在植入表达 HER2 的 SK-OV-3 肿瘤细胞和人外周血单核细胞的人源化小鼠模型中，PRS-343 导致肿瘤生长抑制和肿瘤浸润淋巴细胞的剂量依赖性增加。在 IND 许可研究中，发现 PRS-343 具有良好的耐受性，没有明显的毒性，也没有与药物相关的毒性发现。
PRS-343 通过双特异性结合 HER2 和 4-1BB 促进肿瘤局部 T 细胞的靶向。与当前的单特异性方法相比，这种方法有可能提供更局部的免疫系统激活，具有更高的疗效和降低的外周毒性。报告的数据导致了首例此类分子的 I 期临床试验的启动。
