CD73, also known as Ecto-5′-Nucleotidase, is a cell surface enzyme, which is widely expressed on the surface of endothelial cells of human bodies, lymphocytes such as Treg and other cells. CD73 is overexpressed in tumor microenvironment, and CD39-CD73 passage can help to transform the ATP with immune activation into adenosine and then promote tumor growth.
In tumor microenvironment, the up-regulation of CD73 expression will increase the amount of adenosine, which can promote tumor growth and disease progression: the cytotoxicity of T cells and NK cells and the production and proliferation of cytokines are inhibited, thus the antigen presenting cells (APC) are inhibited as well. The proliferation of Treg cells and is promoted and immune competence is prohibited. The polarization of MDSC and M2 macrophages is promoted.
Preclinical studies have shown that CD73 expressed on the surface of tumor cells is one of the reasons of tumor immune escape. Inhibiting CD73 may stimulate the activity of T cell and enhance anti-tumor immune monitoring at the level of T cells and other immune cells regulated by adenosine. Studies have proved that CD73 antibody is positively effective and safe for solid tumors. Therefore, more and more pharmaceutical companies are committed to the development of CD73 target drugs, including those in China. Let's take a look at three leading Chinese pharmaceutical companies.
Henlius
On June 1, Henlius announced that the clinical trial application of its self-developed innovative monoclonal antibody HLX23 (recombinant anti-CD73 fully humanized monoclonal antibody injection) was approved by the US Food and Drug Administration (FDA), which will be expected for the treatment of advanced solid tumors. In addition, early clinical data show that its monotherapy or combined immunization checkpoint inhibitors such as anti-PD-1/L1 monoclonal antibody have good security and significant anti-tumor effect for solid tumors such as colorectal cancer and pancreatic cancer.
HLX23 can specifically bind to CD73 on the surface of cancer cells, inhibit the nucleotidase function of CD73, promote endocytosis of CD73, and inhibit tumor growth. Preclinical pharmacological, pharmacokinetic and safety studies suggest that HLX23 is well tolerated and safe inside animals.
I-MAB Biopharma
On May 20, I-MAB Biopharma announced that it would publish the data of Phase 1 clinical research of its CD73 antibody uliledlimab (TJD5) in the United States in the annual meeting of American Society of Clinical Oncology (ASCO) in 2021. What is worth mentioning is that the clinical research results have also been successfully included into the "Top 12" research abstract of this year's ASCO conference.
Uliledlimab is a highly differentiated humanized monoclonal antibody CD73 independently developed by I-MAB Biopharma. This drug candidate can effectively bind to CD73 in a non-substrate competitive way to reduce the adenosine level and improve anti-tumor immune cell activity.
According to the data of Phase 1 clinical trial in the United States to be released by I-MAB Biopharma at the ASCO conference, the combination of uliledlimab with PD-L1 inhibitor Atezolizumab has shown perfect security in the treatment of advanced cancer patients, and there is no dose-limiting toxicity (DLT) events. The treatment-related adverse events are only grade 1 or 2. At medium/high dose levels (≥10mg/kg), the pharmacokinetic (PK) characteristic of uliledlimab is linear, and the peripheral blood solubility or CD73 of cell surface have all reached complete receptor occupation.
Among 13 assessable patients who received a dose of ≥10 mg/kg uliledlimab, 3 patients achieved complete or partial response (objective response rate was 23%) after receiving treatment, including one failed case receiving treatment with Ni-vo-lu-mab, and another 1 case of complete response patient receiving combined treatment of uliledlimab and Atezolizumab for 17 months. Meanwhile, the experim...
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