Introduction to AMG 404 (Zeluvalimab)
AMG 404, also known as zeluvalimab, is a human IgG1 monoclonal antibody developed by Amgen. As an investigational immune checkpoint inhibitor, it represents a form of immunotherapy aiming to leverage the body's immune system to combat cancer. While chemotherapy directly targets cancer cells, AMG 404 intervenes in the immune regulatory process. Its development, still primarily in the research phase, is a key area of focus in oncology.
The Mechanism of Action: How AMG 404 Works
AMG 404's therapeutic effect stems from its precise action within the immune system, specifically by targeting a mechanism cancer cells use to evade immune detection. This involves several steps:
- Targeting the PD-1 Receptor: AMG 404 is designed to bind to the programmed cell death protein 1 (PD-1) receptor on T-cells, which normally acts as an immune system brake.
- Blocking the PD-1/PD-L1 Pathway: By blocking the interaction between PD-1 on T-cells and PD-L1/PD-L2 on cancer cells, AMG 404 removes the inhibitory signal that allows cancer cells to escape immune responses.
- Restoring Immune Function: This blockage reactivates T-cells, allowing them to identify and attack cancer cells, thereby initiating an anti-tumour immune response.
Clinical Development and Research Findings
Amgen has conducted clinical trials to assess AMG 404's safety, tolerability, and efficacy. These studies have provided valuable data on its potential.
Phase 1 Study in Advanced Solid Tumours
A first-in-human Phase 1 study (NCT03853109) evaluated AMG 404 monotherapy in patients with various advanced solid tumours. The study reported that the drug was tolerable at tested doses, with fatigue and pruritus being the most common treatment-related adverse events. A dose of 480 mg every four weeks was recommended for Phase 2 studies. Encouraging anti-tumour activity was noted, particularly in patients with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high PD-L1 expression.
Combination Therapy Investigations
AMG 404 has also been investigated in combination with other treatments:
- A Phase 1b study (NCT04524455) combined AMG 404 with blinatumomab for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
- Another study (NCT04885998) explored the combination of AMG 404 and tarlatamab in patients with small cell lung cancer.
Comparison of AMG 404 with Other Anti-PD-1 Therapies
AMG 404 is in the same class as established therapies like pembrolizumab and nivolumab. While they share a common mechanism, there are differences. Amgen's development of AMG 404 was informed by the clinical experience with these existing anti-PD-1 monoclonal antibodies.
| Feature | AMG 404 (Zeluvalimab) | Nivolumab (Opdivo) | Pembrolizumab (Keytruda) |
|---|---|---|---|
| Developer | Amgen | Bristol Myers Squibb | Merck |
| Mechanism | Human IgG1 mAb targeting PD-1 | Human IgG4 mAb targeting PD-1 | Humanised IgG4 mAb targeting PD-1 |
| Development Phase | Investigational (Phase 1 completed) | Approved for numerous indications | Approved for numerous indications |
| Fc Region | Modified for reduced FcγR and complement interaction | Standard IgG4 | Standard IgG4 |
| Dose (Monotherapy) | 480 mg Q4W (recommended Phase 2 dose) | Variable (e.g., 480 mg Q4W) | Variable (e.g., 400 mg Q6W) |
| Status | Primarily for research use | Commercially available | Commercially available |
Potential Side Effects and Safety Considerations
As an immunotherapy, AMG 404 can lead to immune-related adverse events (irAEs) due to the immune system attacking healthy tissues. In the Phase 1 solid tumour trial, the most frequent treatment-related side effects were fatigue and pruritus. Infusion-related reactions are also possible with monoclonal antibodies. Ongoing research continues to monitor and characterize the full safety profile of AMG 404.
Conclusion
In conclusion, AMG 404 (zeluvalimab) is an investigational anti-PD-1 monoclonal antibody that has undergone Phase 1 clinical trials for advanced solid tumours. Its function is to block the PD-1 immune checkpoint, thereby restoring the body's T-cell response against cancer cells. While initial trials demonstrated promising safety and efficacy, particularly in certain patient groups, AMG 404 is not yet approved and remains in the research phase. Its continued development may offer another therapeutic option within cancer immunotherapy. Learn more about clinical trials on ClinicalTrials.gov.
