An Emerging Target for Solid Tumors -- CD73 Development in China

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 experiment also shows that 3 patients with stable diseases (disease control rate of 46%) and the tumor types involved cover ovarian clear cell cancer, non-small cell lung cancer, etc., including but not limited to PD-L1 inhibitor initial treated and refractory cancer patients. 

Antengene 

On May 18, Antengene announced that it had reached an exclusive license agreement with Calithera Biosciences (hereinafter referred to as "Calithera"), a clinical biotechnology and health supply company focusing on developing new small molecule drugs for treating life-threatening diseases such as tumors, on the world-wide development and commercialization of CD73 small molecule inhibitor CB-708 (ATG-037). 

CB-708 is an efficient and highly selective CD73 small-molecule oral inhibitor, which is expected to free up its great potential in monotherapy or combination therapy for various tumors treatments. According to the preclinical data released at the 2019 annual meeting of American Association for Cancer Research (AACR) and 2019 Society for Immunotherapy of Cancer (SITC), the CB-708 monotherapy has immune-mediated activity homologous tumor models of mouse. Preclinical studies show that CB-708 is well tolerated and expresses stronger anti-tumor activity when combined with anti-PD-L1 immunotherapy or chemotherapy drugs (such as ox-ali-pla-tin or adriamycin). Toxicological study on Good Laboratory Practice (GLP) of CB-708 has been completed and the clinical research will be launched soon. 

As a new target for tumor immunity, CD73 is closely related to the occurrence, development, metastasis and poor prognosis of tumors. Preclinical studies have also fully proved that CD73 can advance immune escape of tumors. Drugs targeting CD73 (especially antibody drugs) can inhibit development and metastasis of tumor, and can create synergistic effects when combined with PD-(L) 1 monoclonal antibody and/or A2AR inhibitors. The early confirmatory clinical trials are working in progress. 

According to the features of tumor microenvironment and the mechanism of acquired drug resistance, CD73 has the potential to be combined with more therapeutic strategies, such as radiotherapy and chemotherapy, CTLA-4 monoclonal antibody, adoptive cell therapy, which all need to be verified by clinical trials. 

The developing CD73 target therapies all over the world mainly include CD73 monoclonal antibodies, CD73 double antibodies, and CD73 small-molecule inhibitors. CD73 has become one of the most popular new targets in the market. 

References: 

1. Jiang T, Xu X, Qiao M, et al. Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers[J]. BMC cancer, 2018, 18(1): 1-10.

2. Retrieved May 20, 2021, from https://www.i-mabbiopharma.com/cn/article-639.aspx.

3. Roh, Meejeon, Wainwright,Derek A et al. (2020). Targeting CD73 to augment cancer immunotherapy.Current Opinion in Pharmacology. doi:10.1016/j.coph.2020.07.001.