Preclinical Characterization of a Novel Anti-Cancer PD-L1 Inhibitor RPH-120
| العنوان: | Preclinical Characterization of a Novel Anti-Cancer PD-L1 Inhibitor RPH-120 |
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| المؤلفون: | Andrey Kulikov, Anastasia Dmitrieva, Elena Shipaeva, Vera Batrak, Michael Zhang, Colin Guy, Mikhail Samsonov, Jeff Duan, Ran Zhang, Georgy Shipunov, Yan Lavrovsky, Jill Smith, Sergei Barbashov, Anton Chestukhin |
| المصدر: | Frontiers in Pharmacology, Vol 12 (2021) Frontiers in Pharmacology |
| بيانات النشر: | Frontiers Media SA, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | PD-L1, Pharmacology, cancer immunotherapy, medicine.drug_class, Chemistry, medicine.medical_treatment, Cancer, RM1-950, Mixed lymphocyte reaction, Monoclonal antibody, medicine.disease, in vitro efficacy, Fusion protein, animal models, In vitro, Cancer immunotherapy, monoclonal antibody, In vivo, Atezolizumab, medicine, Pharmacology (medical), therapeutic agent, Therapeutics. Pharmacology, Original Research |
| الوصف: | RPH-120 is a novel fully human anti-PD-L1 IgG1 monoclonal antibody with specifically designed Asn300Ala mutation in Fc fragment. Surface plasmon resonance assay showed that affinity of the RPH-120 to the dimeric form of human PD-L1-Fc fusion protein was much higher than affinity to the monomeric His-tagged PD-L1. Further binding studies demonstrated that RPH-120 is able to bind to human and monkey but not mouse PD-L1. Tissue cross-reactivity study showed good comparability of human and Cynomolgus monkeys tissue staining. Bioactivity was assessed using mixed lymphocyte reaction assay. This study revealed that RPH-120 was able to activate T cells preventing PD1/PD-L1 interaction. Antitumor efficacy was analyzed in HCC-827 lung cancer xenografts in humanized CD34+ mice at three dosage levels: 20, 80, and 200 mg/kg. RPH-120 demonstrated significant tumor growth inhibition, and this inhibition was comparable to that of atezolizumab. In a single dose toxicity, toxicokinetic and dose range finding study performed in Cynomolgus monkeys, RPH-120 was administered via intravenous (IV) bolus or 60-min IV infusion, followed by 8-weeks recovery period. An acceptable toxicokinetic profile was demonstrated and administration at doses of up to 200 mg/kg was well tolerated by all animals. In conclusion, RPH-120 revealed promising in vitro and in vivo activity and safety. RPH-120 is a potent anti-PD-L1 drug candidate for cancer immunotherapy. |
| تدمد: | 1663-9812 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca5ccb0106709018fc75218482361d7dTest https://doi.org/10.3389/fphar.2021.723038Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ca5ccb0106709018fc75218482361d7d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16639812 |
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