Research and Development Status of Multi-Strain LBPs

The interaction between the host and microbiota forms a complex ecosystem between the immune system and microbiota, and immune system dysfunction is the cause of various diseases. Therefore, using microbial intervention for disease treatment has become another new drug development hot spot, and many researchers have started to develop multi-strain LBPs.

Since the early 21st century, CDI has been one of the main global public health problems, and microbiota therapy based on fecal microbiota transplants (FMT) has shown significant efficacy in clinical trials for CDI. SER-109 is a microbiota therapy composed of purified thick-walled spores, which can effectively treat CDI. The core logic is that the nutrients and bile acids are necessary for the metabolic growth competition of thick-walled spore organisms with C. difficile, thereby inhibiting the reproduction of C. difficile. Phase Ⅲ results showed that SER-109 can significantly reduce the recurrence rate of CDI, and its safety is similar to that of placebo. Similarly, multi-strain LBPs is a broad-spectrum microbial community suspension that can also treat CDI. Compounds secreted by the Clostridium and Lactobacillus strains in this multi-strain LBP can inhibit the growth of C. difficile. In addition, secondary bile acids produced by the metabolism of Clostridium in this multi-strain LBP can enhance the colonization resistance of C. difficile, and non-toxic C. difficile that provides a nutritional ecological niche competition will also inhibit C. difficile infection. This drug has obtained key positive data in phase Ⅲ clinical trials. CP-101 is a capsule-administered microbiota therapy based on freeze-dried feces, which is also used to prevent CDI recurrence, and is currently in phase Ⅱ clinical trials.

Many composite bacterial LBPs are microbial therapy agents isolated from biological samples such as saliva or feces. After these bacteria are isolated, they can be propagated in a clone cell bank. The drug contains 8 symbiotic C. difficile strains that can treat CDI. This multi-strain LBP has achieved the expected effect in phase Ⅱclinical trials, and phase Ⅲ trials are planned to start in 2022. Another drug, is a consortium of 11 bacterial strains isolated from healthy human donor feces, which can induce the activation of CD8⁺ T cells, enhance the immune system's ability to attack tumor cells, and significantly enhance the effect of anti-PD-1 treatment. This drug has made some progress in combination therapy for multiple tumors, and is currently undergoing phase Ⅱ clinical trials to further evaluate its safety, tolerability, and efficacy. Another LBP contains 11 strains of fecal-derived bacteria that can induce immune tolerance by modulating the gut microbiota, and thus treat autoimmune diseases such as inflammatory bowel disease (IBD). In phase Ⅰ clinical trials, this drug has shown good safety and tolerability, and phase Ⅱ clinical trials are currently underway.

In addition, multi-strain LBPs contains 4 natural strains from the human gut, which can enhance the efficacy of immune therapy and promote the body's anti-tumor immune activity through multiple biological processes, thereby inhibiting tumor growth. Researchers are currently conducting phase Ⅰ clinical trials of this drug to further evaluate its safety and tolerability for non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC). Researchers have developed a composite bacterial LBP based on the CORAL platform, which contains 9 carefully selected symbiotic bacteria. In animal models, this drug can improve portal hypertension, insulin signal transduction, non-alcoholic fatty liver activity index, and prevent the development of liver fibrosis. Furthermore, this drug can also improve vascular endothelial function and reshape the gut microbiota.

Although FMT therapy has undergone many clinical trials, scientists have yet to determine its specific mechanism of action, which has certain risks, including unpredictable side effects, unstable efficacy, and regulatory difficulties. In contrast, composite bacterial LBPs composed of clearly defined bacteria combinations are safer, and more controllable, and their mechanisms of action are clearer, making them more acceptable to people.

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