Huaothai's Preclinical Research on HB0045, a CD73 Bispecific Antibody Cocktail, Published in Nature Communications

Good News!HB0045（CD73Preclinical Research Achievements of Cocktail Compound Antibody PublishednatureSub-publication "Nature Communications》

Abstract:

On December 31, 2024, Shanghai Huaota Biopharmaceutical Co., Ltd. (hereinafter referred to as "Huaota"), a subsidiary of Huahai Pharmaceutical Co., Ltd., a biopharmaceutical company dedicated to the innovative research, production, and sales of treatments for major diseases such as cancer and autoimmune disorders, announced that the preclinical study results of its CD73-targeting cocktail compound antibody (research code: HB0045) were published in the prestigious international academic journal, Nature Communications, a subsidiary of Nature. The article is titled “An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control.” Dr. Xiangyang Zhu, CEO of Huaota, Dr. Yifan Zhan, Chief Scientific Officer, and Dr. Li Wan, a researcher at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, are the co-corresponding authors of this article. Dr. Jingen Xu, the project leader, along with Shi Chen and Xi Zhu, are the co-first authors. The entire R&D team of Huaota made significant contributions to this project.

https://doi.org/10.1038/s41467-024-55207-9

Introduction to HB0045 Project:

CD73, also known as ecto-5'-nucleotidase, is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein encoded by the NT5E gene, with its primary function being the catalysis of AMP into adenosine. As shown in Figure 1 below, the structure of CD73 consists of three domains, where the N-terminus contains two Zn ion binding sites, the C-terminus has a substrate AMP binding site, and the N-terminus and C-terminus are connected by a flexible α-helical hinge region. CD73 is anchored to the cell membrane via GPI but can also be cleaved by related enzymes and released into the tumor microenvironment or bloodstream. In recent years, the adenosine signaling pathway, as a component of the tumor microenvironment (TME), has emerged as a crucial regulatory factor in cancer progression. As the main enzyme responsible for catalyzing adenosine production, CD73 is highly expressed on the surface of many tumor cells, inhibiting anti-tumor immune responses and thereby promoting cancer cell proliferation, tumor growth, and metastasis. CD73 has become a highly promising target for cancer therapy in the pharmaceutical industry. According to incomplete statistics, there are nearly a hundred drugs targeting CD73 currently under research and development globally, including monoclonal antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and small molecule drugs. To date, no CD73-targeted drugs have been approved for marketing either domestically or internationally.

Figure 1 Schematic diagram of CD73 structure

HB0045 is a compound preparation independently developed by Huaota, consisting of two monoclonal antibodies, HB0038 and HB0039, which target different epitopes of human CD73, combined in a molar ratio of 1:1. As shown in Figure 2 below, structural analysis indicates that HB0038 can highly specifically bind to the catalytic domain of CD73 formed by the N-terminus and C-terminus, creating steric hindrance to inhibit the hydrolysis of AMP (adenosine monophosphate) in a non-substrate competitive manner, thereby blocking the adenosine pathway. HB0039 can highly specifically bind to the N-terminal region of CD73, inhibiting the conformational change of CD73 from the inactive "open" state to the catalytically active "closed" state, making it an "allosteric inhibitor" of CD73.

Figure 2 Binding mode of HB0045 cocktail compound antibody and CD73

Huaota's R&D team discovered that, in in vitro models, cocktail compound antibodies can enhance the inhibitory effect on both soluble and membrane-bound CD73 enzymatic activity compared to single-component antibodies. This maximizes the blockade of adenosine production and significantly enhances the immune-stimulating function of CD8 and CD4 T cells derived from PBMCs. Additionally, in multiple in vivo tumor models, HB0045 cocktail compound antibody demonstrates stronger anti-tumor growth effects compared to monoclonal antibodies targeting the same site (Figure 3).

Figure 3 HB0045 Cocktail Antibody Can Synergistically Activate T Cells and Enhance Anti-Tumor Effects

Dr. Zhu Xiangyang, CEO of Huaota, commented: "It is a great honor to see the preclinical research results of the HB0045 project published in the authoritative journal *Nature Communications*. This not only indicates that HB0045 has the potential to be the best-in-class but also marks that Huaota's scientific research capabilities have been recognized by top international academic journals, which is inseparable from the years of efforts made by the entire research and development team led by Dr. Zhan Yifan. Huaota will continue to rapidly advance the Phase I clinical trial of HB0045 and actively explore its synergistic effects with other targets inside and outside the pipeline, broaden the scope of indications, and look forward to bringing better treatment options to more cancer patients in the future."

About Huaota:

Huaota is a biopharmaceutical R&D company that focuses on independent development and has a global outlook. Specializing in the R&D of biologics for oncology, autoimmune diseases, and retinal disorders, the company currently has 11 projects in clinical stages: including an IL-36R monoclonal antibody for generalized pustular psoriasis (a rare disease), which is soon to enter pivotal Phase II trials as the first self-developed treatment in China; a PD-L1/VEGF bispecific antibody already in Phase II clinical trials, showing promising signals in endometrial cancer and renal cell carcinoma; and a core project featuring CD73-ADC, the first drug with dual cytotoxic mechanisms targeting difficult-to-treat cancers such as pancreatic cancer.

Huaota is currently actively seeking partners both in China and internationally to jointly advance and co-develop, aiming to provide high-quality, high-level biopharmaceuticals to the global market. This effort seeks to meet the vast patient demand for accessible and affordable biologics, fulfilling the vision of innovation changing the world!