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- Title
A Novel Monoclonal Antibody against PD-1 for the Treatment of Viral Oncogene-Induced Tumors or Other Cancer.
- Authors
Xu, Xu; Yan, Shih-Long; Yo, Yi-Te; Chiang, Peiyu; Tsai, Chan-Yen; Lin, Lih-Ling; Qin, Albert
- Abstract
Simple Summary: Viral infection poses cancer risk and the PD-1/PD-L1 immune check point plays a critical role in this process. Despite the success of the existing anti-PD-1 and PD-L1 antibodies, significant challenges remain due to drug resistance and serious side effects. We have developed a novel anti-PD-1 antibody P1801 which has significant PD-1 blocking and antitumor activities. It displayed unique binding properties distinctive from pembrolizumab and nivolumab with limited ADCC- and CDC-mediated lysis of normal immune cells. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, a new-generation interferon-alfa-based therapy which also has antiviral and antitumor activities, for the treatment of cancer. Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) interact to form an immune checkpoint fostering viral infection and viral oncogene-induced tumorigenesis. We generated a novel anti-human PD-1, humanized monoclonal antibody P1801 and investigated its pharmacologic, pharmacokinetic (PK), and pharmacodynamic properties. In vitro binding assays revealed that P1801 uniquely binds to human PD-1 and inhibits its interaction with PD-L1/2. It showed a minor effect on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). P1801 significantly induced the release of IL-2 from activated T-cells but not from nonactivated T-cells. A dose-dependent linear PK profile was observed for the cynomolgus monkeys treated with repeated doses of P1801 at 5 mg/kg to 200 mg/kg once weekly. A four-week repeat-dose toxicity study revealed that P1801 given weekly was safe and well tolerated at doses ranging from 5 to 200 mg/kg/dose. No pathological abnormalities were noted. In humanized PD-1 mice harboring human PD-L1-expressing colon tumor cells, P1801 administered intraperitoneally twice per week at 12 mg/kg significantly inhibited tumor growth and prolonged mouse survival. P1801 displayed unique binding properties different from pembrolizumab and nivolumab. Therefore, it showed distinctive immunological reactions and significant antitumor activities. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, which also has antiviral and antitumor activities, for the treatment of cancer.
- Subjects
THERAPEUTIC use of monoclonal antibodies; IN vitro studies; BIOLOGICAL models; RESEARCH funding; PROGRAMMED death-ligand 1; ANTINEOPLASTIC agents; COLORECTAL cancer; DESCRIPTIVE statistics; MONOCLONAL antibodies; ANTIVIRAL agents; MICE; ONCOGENES; DRUG interactions; ANIMAL experimentation; PRIMATES
- Publication
Cancers, 2024, Vol 16, Issue 17, p3052
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16173052