Bispecific anti-PD-1/PD-L1 antibody CTX-8371 to promote cellular clustering and PD-1 shedding, antitumor activity and tolerability
| العنوان: | Bispecific anti-PD-1/PD-L1 antibody CTX-8371 to promote cellular clustering and PD-1 shedding, antitumor activity and tolerability |
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| المؤلفون: | Xianzhe Wang, Diana I. Albu, Bing Gong, Vivian Li, Taeg Kim, Yan Qin, T. Schuetz, Nelly Kuklin |
| المصدر: | Journal of Clinical Oncology. 39:e15056-e15056 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Antitumor activity, Cancer Research, biology, business.industry, Anti pd 1, Pharmacology, Blockade, Oncology, Tolerability, PD-L1, biology.protein, Medicine, Antibody, business |
| الوصف: | e15056 Background: Checkpoint blockade therapies targeting PD-1 and PD-L1 have shown great success for the treatment of various malignancies. However, a substantial fraction of patients with PD-L1-positive tumors remain unresponsive to these therapies. Novel therapy with significantly greater activity than the leading PD-1/PD-L1 inhibitors is expected to bring additional clinical benefit to patients. Here we describe the preclinical evaluation of CTX-8371, which combines anti-PD-1 and anti-PD-L1 monoclonal antibodies in one bispecific tetravalent molecule. Methods: The immune-enhancing activity of CTX-8371 was tested in vitro in T cell activation assays and tumor cell killing assay. CTX-8371 anti-tumor efficacy in vivo was assessed using mouse tumor cells expressing human PD-L1 implanted in transgenic mice humanized at the PD-1 and PD-L1 loci. CTX-8371 anti-tumor activity was also tested in xenograft tumor models. The mechanism of action of CTX-8371 was investigated in vitro using Jurkat cells expressing PD-1 or PD-L1, human PBMCs, and in vivo in tumor-bearing, chimeric PD-1/PD-L1 transgenic mice. CTX-8371 PK was determined in mice using an MSD ELISA-based assay and in cynomolgus monkeys using a qualified ELISA method. Dose range finding and toxicokinetic studies were performed in cynomolgus monkeys. Results: CTX-8371 potently enhanced T cell activation and function in vitro and showed curative efficacy as monotherapy in multiple solid tumor models, isografts or xenografts. Furthermore, CTX-8371 demonstrated superior anti-tumor efficacy compared to Keytruda or atezolizumab in checkpoint inhibitors-sensitive and resistant syngeneic mouse tumor models. Mechanistically, in addition to blocking PD-1 interaction with PD-L1, CTX-8371 bispecific antibody facilitated cell to cell bridging between cells expressing PD-1 and cells expressing PD-L1. Furthermore, we show that simultaneous binding of CTX-8371 to both PD-1 and PD-L1 resulted in long term PD-1 shedding. This suggests that CTX-8371 may prevent or overcome T cell exhaustion within the tumor microenvironment, thus providing additional advantage over existing therapies. Lastly, excellent tolerability was observed in non-human primates given 2 weekly drug infusions at up to 50 mg/kg dose. Conclusions: CTX-8371 displays multiple mechanisms of action over monoclonal PD1/PD-L1 blockade. These unique pharmacological properties of CTX-8371 could explain the enhanced T cell responses to tumor antigens and superior efficacy over current monoclonal antibody therapies. With favorable PK/PD and toxicology profiles in mice and cynomolgus monkeys, CTX-8371 warrants further advancement to clinical testing. |
| تدمد: | 1527-7755 0732-183X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::625d4d12ebf52730edd2131c6d2fc6ad https://doi.org/10.1200/jco.2021.39.15_suppl.e15056 |
| رقم الأكسشن: | edsair.doi...........625d4d12ebf52730edd2131c6d2fc6ad |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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