Tremelimumab is marketed by name, Imjudo. It is a CTLA-4 inhibitor that has been approved for the treatment of unresectable HCC and non-small-cell carcinoma.
What is CTLA-4?
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a protein receptor that is expressed on the surface of T-cells (a type of immune cell).
It functions as a negative regulator of T-cell activation and helps to prevent excessive immune responses. By binding to its ligands (B7-1 and B7-2) on antigen-presenting cells, CTLA-4 downregulates T-cell activation and proliferation, leading to a reduction in cytokine production and T-cell-mediated immune responses.
CTLA-4 is also a target for cancer immunotherapy, as blocking its function can enhance the activation and proliferation of T-cells, which may help to fight against tumors.
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List of CTLA-4 Inhibitors:
The following are CTLA-4 inhibitors:
- Ipilimumab (brand name Yervoy)
- Tremelimumab
- Abatacept (brand name Orencia, used for rheumatoid arthritis) – acts as a selective CTLA-4 inhibitor.
FDA-Approved Indications of CTLA-4 Inhibitors:
FDA-approved indications for the three CTLA-4 inhibitors:
Ipilimumab (Yervoy):
- Metastatic melanoma
- Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy
Tremelimumab (Imjudo):
- Unresectable hepatocellular carcinoma
- Non-small cell lung cancer
Abatacept (Orencia):
- Rheumatoid Arthritis
- Juvenile Idiopathic arthritis
- Psoriatic arthritis
- Ankylosing spondylitis
- Systemic lupus erythematosus
- Non-radiographic spondyloarthritis
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Tremelimumab MOA (Mechanism of Action):
Tremelimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of T-cell activation.
Tremelimumab binds to CTLA-4 and prevents its interaction with its ligands, CD80 and CD86, on antigen-presenting cells (APCs).
By blocking this interaction, Tremelimumab enhances the activation and proliferation of T cells, which can lead to an enhanced antitumor immune response.
CTLA-4: A key regulator of the immune system:
CTLA-4 is a key regulator of the immune system that inhibits T-cell activation and prevents autoimmunity. It is expressed on the surface of activated T cells and regulatory T cells (Tregs).
CTLA-4 binds to CD80 and CD86 on APCs with higher affinity than the co-stimulatory molecule CD28, which is required for T-cell activation.
This interaction inhibits T-cell activation and promotes the differentiation of Tregs, which suppress the immune response.
Tremelimumab binds to the extracellular domain of CTLA-4 and blocks its interaction with CD80 and CD86.
By preventing this interaction, Tremelimumab enhances the activation and proliferation of T cells, which can lead to an enhanced antitumor immune response.
In addition, Tremelimumab can reduce the number and suppressive function of Tregs, which can further enhance the antitumor immune response.
Targeting Tregs:
Tregs are a subset of T cells that play a critical role in maintaining immune tolerance and preventing autoimmunity.
They express high levels of CTLA-4 and are known to suppress the activation and proliferation of effector T cells.
In the tumor microenvironment, Tregs can suppress the antitumor immune response and promote tumor growth.
Tremelimumab can reduce the number and suppressive function of Tregs by blocking the interaction of CTLA-4 with CD80 and CD86.
This can enhance the activation and proliferation of effector T cells and promote an antitumor immune response.
Tremelimumab in Clinical Trials:
Tremelimumab has been shown to enhance the antitumor immune response in preclinical models and clinical trials.
In a phase I trial of patients with advanced melanoma, Tremelimumab treatment resulted in objective responses in 17% of patients and disease stabilization in an additional 23% of patients.
In a phase III trial of patients with advanced melanoma, Tremelimumab treatment did not improve overall survival compared to chemotherapy, but it did improve overall survival in a subset of patients with a low baseline lactate dehydrogenase level.
Tremelimumab Plus Durvalumab:
Tremelimumab has also been evaluated in combination with other immune checkpoint inhibitors, such as durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody.
The combination of Tremelimumab and durvalumab has shown promising antitumor activity in patients with advanced solid tumors, including melanoma, non-small cell lung cancer, and bladder cancer.
In a phase III trial of patients with unresectable hepatocellular carcinoma, the combination of Tremelimumab and durvalumab improved overall survival compared to sorafenib, a standard-of-care therapy for advanced hepatocellular carcinoma.
In Summary:
Tremelimumab is a fully human monoclonal antibody that targets CTLA-4, a negative regulator of T-cell activation.
Tremelimumab blocks the interaction of CTLA-4 with CD80 and CD86 on APCs, which enhances the activation and proliferation of T cells and reduces the suppressive function of Tregs.
Tremelimumab has shown promising antitumor activity as a monotherapy and in combination with other immune checkpoint inhibitors in clinical trials.
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