The new genetic engineering drug SalMet-Vec® developed by Sinogen Pharmaceutical was published in the journal of Cell Reports Medicine

Introduction: Malignant tumors are currently one of the main causes of disease death worldwide, and there is an urgent need to develop more effective innovative therapies and drugs. The combination of tumor bacterial therapy and metabolic therapy will provide new strategies for tumor treatment.

June 2, 2023,published by PHARNEX--- Guangzhou Sinogen Pharmaceutical Co., Ltd. (referred to as Sinogen Pharmaceutical), along with collaborators from multiple institutions such as Guangdong University of Technology and Nanjing Medical University, jointly published a research paper titled "Targeted Deprivation of Medicine with Engineering Salmonella Leads to Oncology and Suppression of Metastasis in Broad types of Animal Tumor Models" online in the international academic journal Cell Reports Medicine (IF: 16.988). The research paper reported the development process of the genetic engineering oncolytic bacteria SalMet-Vec^® targeting the regulation of tumor methionine metabolism, and explored its potential clinical transformation value, demonstrating the role of tumor lysis and tumor metastasis inhibition in the treatment of broad-spectrum malignant tumors.

Dr. Allan Zijian Zhao, Chairman and CEO of Huajin Pharmaceutical (co-author of the paper), said in an interview with Xinhua News Agency: "The strong demand for methionine is a common feature of almost all types of tumors, and cancer cell metastasis is the main reason for shortening the lifespan of cancer patients. SalMet-Vec® will provide a new treatment method for cancer patients and extend their life.”

01 Research Background

Unlike normal cells, most tumor cells and tumor stem cells are methionine dependent. Based on this characteristic, researchers limit the intake of methionine in the diet of cancer patients, administer methionine enzymes to specifically consume methionine in the body, or treat tumors by targeting the methionine metabolic pathway. The utilization of methionine enzyme to hydrolyze methionine may be a highly promising pathway for the development of broad-spectrum anti-tumor drugs. However, when administered intravenously, amino acid enzyme drugs represented by methionine enzymes have poor stability and high immunogenicity in the serum, which limits their clinical use. To further enhance drug targeting, extend drug half-life, and reduce other adverse reactions, it is necessary to utilize new drug delivery systems.

More than 100 years ago, William Coley, the "father of cancer immunotherapy" and a New York bone surgeon in the United States, treated over 1000 sarcoma patients by injecting bacteria, some of whom had their malignant tumors eradicated. However, due to the high toxicity of bacteria and the rise of radiation and chemotherapy methods, tumor bacterial therapy has gradually faded out of the historical stage. In recent decades, with the acquisition of  multiple attenuated strains through genetic engineering technology, breakthrough progress has been made in tumor bacterial therapy. Although the complex tumor microenvironment (hypoxia, low pH, etc.) greatly impedes the delivery of drugs, it is the basis for bacteria to target solid tumors. Bacteria can chemically target solid tumor sites and reproduce in tumors to stimulate anti-tumor immunity. Salmonella typhimurium is an ideal drug delivery system for tumor treatment.

02 Research Process
Dr. Allan Zijian Zhao's team from Sinogen Pharmaceutical, based on the tumor methionine dependence and tumor targeting characteristics of Salmonella, developed the oncolytic bacterium SalMet-Vec^® using attenuated Salmonella VNP20009, which has been clinically proven to be safe for humans, as a vector for high expression of methionine enzymes. Research has confirmed that SalMet-Vec^® can selectively and continuously consume methionine in tumor tissue, achieving the effects of killing tumors and inhibiting tumor spread. In the pre-clinical human tumor transplantation model, SalMet-Vec^® has a strong inhibitory effect on the growth and metastasis of a variety of tumors, including but not limited to small cell lung cancer, osteosarcoma, hepatocellular carcinoma, breast cancer (including triple negative breast cancer), pancreatic cancer, prostate cancer and cervical cancer. In the IIT study, SalMet-Vec^® significantly reduced or completely dissolved the patient's tumor. The patient did not show any serious adverse reactions except for some temporary fevers and nausea.

03 Research Significance

SalMet-Vec^® has completed a series of safety evaluations and can be administered through various methods such as intravenous, intratumoral, and interventional therapy. Due to the dependence of most tumors on methionine, SalMet-Vec^® is a broad-spectrum anti-tumor drug that fills the gap in the current difficulty of tumor therapy drugs entering solid tumors. SalMet-Vec^® can also be used in combination with other current anti-tumor methods to achieve rapid treatment of diseases. It is a candidate new biological anti-tumor drug with fast and broad-spectrum tumor lysis ability.

04 ASCO Publication

During the same period, the SalMet-Vec^® research abstract titled "Oncolytic bacteria, SalMet-Vec^®, Exhibits Rapid Oncolytic Effects against A Broad Spectrum of Malignancies in Pre-clinical and Clinical Studies (NCT05103345 & NCT05038150)" was also included and published online at the 2023 American Society of Clinical Oncology (ASCO) annual meeting. （https://meetings.asco.org/abstracts-presenta  tions/225156）

At present, there are two clinical trials (NCT05103345 and NCT05038150) of SalMet-Vec^® are being conducted in the United States and Taiwan, China, China, for intravenous administration and intratumoral administration of broad-spectrum malignant tumors. SalMet-Vec^® also has obtained two Orphan Drug Designition granted by the U.S. Food and Drug Administration (FDA) for osteosarcoma and hepatocellular carcinoma (HCC) in 2022. As a candidate first-in-class new drug, the oncolytic bacteria SalMet-Vec^® has tumor targeting and methionine hydrolysis ability, showing broad spectrum anti-tumor activity, and has great application potential in the field of tumor treatment.

Dr. Allan Zijian Zhao also stated that "SalMet-Vec^® will conduct clinical trials targeting various types of tumors, especially malignant tumors with limited treatment options, in order to extend the lives of cancer patients worldwide.”

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