Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer

Lou, Beilei; Wei, H.; Yang, Fang; Wang, Shicong; Yang, Baotian; Zheng, Yong; Zhu, Jiman; Yan, Shaoyu

doi:10.3389/fonc.2021.736955

Cited by 19 publications

(11 citation statements)

References 33 publications

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“…In phase II clinical trials of cervical cancer, the objective response rate in patients with PD-L1positive cervical cancer was 26.83%. [8][9][10] However, the PD-L1positive rate varies according to the histological subtype of cervical cancer. PD-1 positivity was found in 37.8% of squamous cell carcinomas, 28.6% of adenosquamous carcinomas, and 16.7% of endocervical adenocarcinomas in 1 investigation of cervical malignancies.…”

Section: Discussionmentioning

confidence: 99%

Whether specific genetic feature predicted immunotherapy efficacy: A case report

Chen,

Pang,

et al. 2024

Medicine

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Rationale: Blockade of programmed death protein 1 (PD-1), have been observed to have quite good efficacy in recurrent and metastatic cervical cancer. Generally, we believe that the biomarkers of PD-1 inhibitors are programmed cell death-ligand 1, tumor mutational burden, high microsatellite instability, or deficient mismatch repair. However, in the case reported below, we observed that the patient with negative existing predictive biomarkers have significant benefits after zimberelimab monotherapy, indicating that there were other biomarkers that may predict immunotherapy efficacy. However, currently, no one has explored and studied the other potential biomarkers of PD-1 inhibitors. Patient concerns: A 51-year-old patient, diagnosed with cervical adenocarcinoma nearly 11 years ago, requested treatment. Diagnoses: The next-generation sequencing has shown PIK3CA E545K, SMAD4 1309-1G, and ALK E717K gene mutations, receptor tyrosine kinase 2 (ErbB-2) amplification, microsatellite stability, and low tumor mutational burden of 6.3 mutations per megabase. And immunohistochemistry revealed that the tumor was programmed cell death-ligand 1 negative. Intervention: Zimberelimab monotherapy was accepted as third-line treatment. Outcomes: The patient had received zimberelimab for nearly 10 months, the best tumor response was PR (Response Evaluation Criteria in Solid Tumours) and no noticeable adverse reactions were observed. Lessons: PIK3CA-E542K, ErbB2 amplification, and SMAD4 mutations could be potential biomarkers for PD-1 inhibitors, but a single instance is insufficient to validate the hypotheses. A larger number of patients or more clinical data will be necessary to determine whether these gene mutations are appropriate biomarkers for patients when treatment with PD-1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Whether specific genetic feature predicted immunotherapy efficacy: A case report

Chen,

Pang,

et al. 2024

Medicine

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“…Sintilimab is a fully humanized IgG4 monoclonal antibody that can bind with PD-1 and specifically block the interaction between PD-1 and its two known ligands, PD-L1 and PD-L2, thereby helping to restore the anti-tumor effect of T cells [ 3 - 5 ]. In vitro experiments, sintilimab demonstrated high affinity and specificity for human PD-1 and effectively inhibited the binding of human PD-1 to PD-L1 and PD-L2 [ 6 ]. ICIs can augment the risk of autoimmune toxicities, resulting in immune-related adverse events (IrAEs) [ 1 , 2 ].…”

Section: Discussionmentioning

confidence: 99%

Hypophysitis Induced by Sintilimab in the Treatment of Bladder Cancer: A Case Report

Li,

Jiang,

Zhu

et al. 2024

EMIDDT

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Background: Immune checkpoint inhibitors (ICIs), as novel antitumor drugs, have been widely used in the clinic and have shown good antitumor effects. However, their widespread use has also led to the emergence of various immune-related adverse events (IrAEs). Hypophysitis is a rare but serious IrAE. Due to its complex and changeable clinical manifestations, hypophysitis may be easily overlooked, leading to delayed diagnosis and treatment. Case Presentation: A 68-year-old male patient was diagnosed with bladder cancer (T2bNXM0) in October 2021. He received two cycles of immunotherapy with sintilimab and chemotherapy with gemcitabine and cisplatin (GC). One month after the second treatment, he gradually developed recurrent fever, anorexia, drowsiness, and delirium. Laboratory examination revealed hyponatremia, decreased adrenocorticotropic hormone, and hypocortisolemia. The pituitary MRI showed no abnormality. The patient was diagnosed with immunotherapy-induced hypophysitis (IH) caused by sintilimab, leading to downstream endocrine disorders. With hormone replacement therapy, he was in a good mood, had a good appetite, and made an overall recovery. Conclusion: Immunotherapy-induced hypophysitis (IH) can result in a severe adrenal crisis, and prompt recognition and diagnosis are crucial. Clinicians must remain vigilant for the possibility of IH in patients who exhibit recurrent fever, anorexia, cognitive decline, and personality changes following ICI treatment. It is imperative to consider this diagnosis early to initiate appropriate management promptly.

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“…Indeed, ADA were detected in some animals in all groups ( Table S1, Table S3 ). The incidence of ADAs for anti PD-1 antibodies have been reported frequently in several Food and Drug Administration approved products, while Finotonlimab showed similar characteristics as other anti-PD-1 drugs as well [33, 34]. However, the anti-tumor efficacy and safety of Finotonlimab needs to be further confirmed in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Basis of the Efficacy and Pharmacodynamics of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody with Potent Implications for Clinical Benefit

Yang

Guo

et al. 2023

Preprint

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Background: The antibodies of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscapes for patients with cancer. Clinical uses of PD-1 antibodies have greatly improved the overall survival and durable responses in patients across selected tumor types. Methods: We describe the preclinical characterization of Finotonlimab, a humanized anti-PD-1 antibody, by head to head comparison with Nivolumab or Pembrolizumab. Herein, we characterized the in vitro and in vivo efficacy, PK, PD and Fc mediated effector function of Finotonlimab. The single-agent anti-tumor activity of Finotonlimab was evaluated using humanized mouse models and a human PBMC reconstituted mouse model. Furthermore, in cynomolgus monkeys, comparative PK measurements confirmed better PK profiles of Finotonlimab than that of Pembrolizumab and Nivolumab. Results: Our data showed Finotonlimab bind to human PD-1 with significantly high affinity and effectively inhibited its interaction with its ligands, PD-L1 and PD-L2, and thus could effectively stimulate the human T cell functions in vitro and exhibited significant antitumor efficacy in vivo. In addition, Finotonlimab showed minimal impact on Fc receptor dependent effector cell activation, which may contribute to the killing of PD-1+ T cells. In cynomolgus monkeys, Finotonlimab exhibited a non-linear pharmacokinetics (PK) profile in a dose-dependent manner, and approximately 90% of consistent receptor occupancy period was observed at 168 h after a single administration of 1 mg/kg. Following a 13-week successive administration of Finotonlimab, a pharmacodynamics study indicated a sustained mean receptor occupancy of ≥ 93% of PD-1 molecules on circulating T cells in cynomolgus monkeys up to 8 weeks even at 3 mg/kg. Conclusions: Taken together, these preclinical data are encouraging and provide a basis for the efficacy and pharmacodynamics of Finotonlimab in clinical trials.

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Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer

Cited by 19 publications

References 33 publications

Whether specific genetic feature predicted immunotherapy efficacy: A case report

Whether specific genetic feature predicted immunotherapy efficacy: A case report

Hypophysitis Induced by Sintilimab in the Treatment of Bladder Cancer: A Case Report

Preclinical Basis of the Efficacy and Pharmacodynamics of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody with Potent Implications for Clinical Benefit

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