Status of NKG2A-targeting drugs under research—PART II

Posted by beauty33 on March 1st, 2022

Autoimmune diseases

NKG2A expression was found to be downregulated in the bodies of autoimmune disease patients. NKG2A-CD94 receptor was highly expressed by NK cells in patients with rheumatoid arthritis\' knee synovial fluid; NKG2A was downregulated on the surface of circulating NK cells in patients with psoriasis; and NKG2A was downregulated on the surface of T cells in patients with systemic lupus erythematosus\' peripheral blood.

Although the safety profile of Innate Pharma\'s NKG2A antibody monalizumab in the treatment of rheumatoid arthritis was good, the endpoints related to rheumatoid arthritis were not fulfilled, according to the results of the Phase I/II clinical study (NCT 01370902).

Antibodies against NKG2A

Innate Pharma and AstraZeneca co-developed Monalizumab (IPH2201), an NKG2A antibody monoclonal antibody that blocks the interaction of NKG2A with HLA-E. NKG2A antibody provides a therapeutic impact in a leukemia mouse model, according to E. Ruggeri L in Haematologica 2016. Monalizumab, a therapeutic drug for the treatment of female reproductive malignancies, has also reached phase II clinical trials. Monalizumab (10 mg/kg) given intravenously every two weeks has demonstrated to have good therapeutic effects and even short-term disease stability. In addition, Monalizumab in combination with cetuximab (EGFR blocking antibody) for recurrent or metastatic head and neck squamous cell carcinoma was effective up to 27.5%, with a median progression-free survival of 5.0 months and a median overall survival of 10.3 months.

Monalizumab is also used in combination with anti-EGFR, anti-PD-L1, tyrosine kinase inhibitors, and chemotherapeutic agents in a variety of cancer indications, including resectable non-small cell lung cancer (NCT 03794544), patients with PD-1 resistant non-small cell lung cancer (NCT 03833440), patients with advanced head and neck squamous cell carcinoma (NCT 02643550), refractory chronic lymphocytic leukemia (NCT 02557516), other malignant hematologic diseases after stem cell transplantation (NCT 02921685), and a trial targeting advanced solid malignancies (NCT 02671435). The NCT 02671435 trial reported safety and, in some cases, durable effectiveness in patients with microsatellite stable colorectal cancer treated with FOLFOX chemotherapy and blocking VEGF, PD-L1 antibody and Monalizumab.

Medimmune used FOLFOX and duvalbuterol (anti-PD-L1), as well as monalizumab, in a larger phase II trial (NCT 04145193) for high-risk microsatellite stable colorectal cancer patients undergoing radical surgery, but the clinical results were unsatisfactory, with only 3 of 39 patients effective, and the trial was halted.

Bristol-Myers Squibb has also developed an NKG2A monoclonal antibody, BMS-986315, which is currently in clinical phase Ib/II using it alone or in combination with cetuximab and Nivolumab for the treatment of advanced solid tumors (NCT 04349267).

Prospects

Available clinical trials have shown that NKG2A inhibitors are effective in inhibiting tumor escape from NK and T cell immune examination. NKG2A inhibitors in combination with other antibodies fared better in some trials, particularly in patients with metastatic colorectal cancer or head and neck cancer. However, larger clinical trials are needed to validate the marketing of NKG2A inhibitors.

The researchers also discovered that using therapeutic cancer vaccines enhanced the number of cytotoxic T lymphocytes. This shows that we might be able to treat a range of cancers by combining NKG2A inhibiting antibodies with cancer vaccine.