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First time Demonstrated: No ADCC effect CTLA4 antibody clinical OS benefit
First time Demonstrated: No ADCC effect CTLA4 antibody clinical OS benefit. On May 7, 2021, AstraZeneca announced the results of the Phase III clinical trial of POSEIDON. Imfinzi, tremelimumab combined with chemotherapy have made positive progress in first-line stage IV (metastatic) non-small cell lung cancer.
The first phase III trial showed an overall survival benefit of tremelimumab.
Compared with chemotherapy alone, the overall survival (OS) benefit of the combination therapy is statistically significant. According to a previous report in October 2019, the immunotherapy combination also showed a statistically significant improvement in progression-free survival (PFS) compared to chemotherapy alone. The security is equivalent.
Although Imfinzi single-agent combined chemotherapy showed a progression-free survival benefit, the overall survival trend did not reach statistical significance.
Imfinzi (durvalumab) is a PD-L1 antibody that can bind to PD-L1 and block the interaction of PD-L1 with PD-1 and CD80.
Tremelimumab is a CTLA-4 antibody that blocks the activity of CTLA-4, promotes T cell activation, triggers an immune response against cancer and promotes cancer cell death. Tremelimumab is an IgG2 subtype and does not have ADCC effects.
This is also the first CTLA-4 antibody with no ADCC effect and has achieved clinically positive results.
Regarding the CTLA-4 antibody, the development concepts in recent years have mostly focused on using it to kill Treg to achieve anti-tumor effects. The development of the second-generation CTLA-4 antibody also enhances the Fc effect and enhances the ADCC effect.
The clinical success of AstraZeneca shows that blocking CTLA-4 itself has a certain anti-tumor effect. The PD-1/CTLA-4 double antibody is supported by clinical data. Significant.
At the same time, AstraZeneca has also developed the PD-1/CTLA-4 dual antibody, MEDI5752, and published an article “Design and efficacy of a Monovalent Bispecific PD-1/CTLA-4 antibody That” in “CANCER DISCOVERY” in May 2021. “Enhances CTLA-4 Blockade on PD-1+ activated T cells” elaborated on pre-clinical research.
Compared with PD-1−T cells, MEDI5752 preferentially binds to CTLA4 on PD-1+ T cells. At the same time, it leads to rapid endocytosis and degradation of PD-1.
Compared with the combination of monoclonal antibodies targeting PD-1 and CTLA4, MEDI5752 preferentially accumulates in tumors and enhances anti-tumor activity. The effect of the medicine in the body is shown in the figure below.
(source:internet, reference only)