From Bugs to Drugs: Harnessing the Power of Microbes as Living Medicines
With the rise in probiotic awareness and evidence indicating the potential therapeutic benefits of certain bacterial strains, live biotherapeutic products (LBPs) are at the forefront of innovative, biotechnology-driven drug development. Although the global market is currently dominated by North American and European firms, significant growth opportunities are anticipated in Asia as LBPs are garnering increasing interest from research institutions and private investors in the region. This perspective explores some of the latest research findings, the current market landscape, the challenges faced by developers in bringing these novel therapeutics to the market, and the outlook of LBPs in Asia.
Since ancient times, microbes have been recorded as agents of destruction that decisively contributed to terrible episodes of history, including but not limited to the Black Plague, the 1918 Spanish flu, and the recent COVID-19 pandemic. Despite the devastating effects of disease-causing microorganisms, “life would not long remain possible in the absence of microbes,” as French biologist Louis Pasteur once said.1 Through technological advancements and developments in biomedical science, our understanding of microorganisms has evolved from viewing them merely as health threats to recognising their importance in supporting human health. Since the completion of the Human Microbiome Project, which uncovered the astounding quantity and diversity of microbial communities inhabiting the human body,2 there has been an exponential increase in research to better understand the intricate host-microbiota interactions that contribute to the development and progression of various diseases.3,4
Recently, the scientific community has demonstrated a growing interest in the therapeutic potential of selected microorganisms and the possibility of engineering them to develop a new class of medicine. Studies indicate that LBPs are a promising treatment for not only gastrointestinal disorders,5 but also cancer, metabolic disorders, and neurological disorders among others.6,7 However, as the field of LBPs is still in its infancy, there are questions surrounding the safety, efficacy, and standardisation of LBPs that have yet to be answered. In fact, the definition of LBP was only established by the US Food and Drug Administration (FDA) less than a decade ago.
What are LBPs?
According to a guidance document issued by the FDA in 2016, LBPs are defined as a biological product that contains live organisms and is developed to prevent, treat, or cure a disease or condition in humans.8 They exclude vaccines, filterable viruses, oncolytic viruses, and organisms used as vectors for gene transfer. Although LBPs differ from traditional probiotics as the latter do not claim to treat or prevent disease, some probiotics can be further developed into or categorised as LBPs if they demonstrate potential efficacy against a disease. Additionally, LBPs that consist of genetically modified organisms may be categorised as recombinant LBPs.9
LBPs are an attractive therapeutic proposition because they not only offer the potential to target different pathways via different modes of action, but in principle, can also be better tolerated than traditional drugs. While traditional drugs often cause off-target delivery and unintended toxicity when systemically administered, microorganisms can deliver therapeutics in a better targeted and more controllable fashion. This is because LBPs normally use niche commensal microbes that inhabit specific target locations of the human body which would enable the administration of higher doses with lower systemic effects.10
Latest Research on LBPs in Asia
In Asia, majority of live biotherapeutic research focuses on identifying bacterial strains with demonstrable therapeutic efficacy on specific diseases and engineering bacteria to equip them with or enhance their therapeutic functions.
One of the most promising areas of research on LBPs in Asia is in the treatment of gastrointestinal diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Compared to conventional treatments that are often ineffective and/or accompanied by severe side effects, recent studies indicate that LBPs may be an effective and safe alternative for the treatment of IBD. Cao et al. demonstrated that a specific strain of Bifidobacterium longum could be engineered to reduce inflammation and treat symptoms in patients suffering from ulcerative colitis.11 Similarly, a randomised controlled trial performed by researchers in Japan reported that a specific strain of B. longum improved constipation in elderly adults.12 Moving away from the lab and closer to real-world practice, Guangzhou Zhiyi Biotech announced in 2022 that their lead product, SK08, developed from Bacteroides Fragilis for the treatment of IBS with diarrhoea, will soon complete Phase II clinical trials.13
Besides gastrointestinal diseases, LBPs are being investigated for their potential in treating and preventing cancer. Using Escherichia coli, Sun et al. innovated a novel strategy called “both-in-one hybrid bacteria” that involves integrating a chemotherapeutic drug onto the bacterial strain to facilitate tumour eradication.14 Ho et al. also showed that engineered commensal microbes can prevent carcinogenesis and encourage the regression of colorectal cancer.15 Furthermore, results from a joint study between researchers in China and Germany confirmed that genetically engineered E. coli Nissle 1917 (EcN), developed for the targeted delivery of cytotoxic compounds, significantly suppressed tumour growth. Therefore, it can potentially be developed to become a novel tumour-targeting therapy system.16
Engineered EcN has also been evaluated to treat metabolic disorders. For instance, Chen et al. demonstrated that administering a specially engineered strain of EcN not only reduced obesity, but also adiposity, insulin resistance, and hepatosteatosis (more commonly known as fatty liver) in mice which were fed a high-fat diet.17 A study carried out by scientists from Taiwan’s National Cheng Kung University also revealed the detailed mechanisms by which specific strains of Ligilactobacillus salivarius and Limosilactobacillus reuteri enhanced glucose tolerance in diabetic mice.18 By engineering EcN to express specific metabolising enzymes, Somabhai et al. also showed how bacteria can be used to manage complications linked to fructose-induced metabolic syndrome like hepatosteatosis.19
Current Market Landscape: The Rise of Start-ups
Given its dynamic research landscape, it is unsurprising that the global LBP market is predicted to increase at a compound annual growth rate of 36 per cent between 2022 to 2031.20 Although the biotherapeutic industry in Asia is relatively nascent as compared to the West, it is rapidly catching up.
In the last decade, there has been a proliferation of innovative biotechnology start-ups. For instance, AsiaBiome, the first microbiome-focused start-up in Asia that was founded in 2016, created a network of more than 8,000 microbiome donors and supported studies on faecal microbiome transplant as an intervention.21 In 2021, List Biotherapeutics, a subsidiary of South Korea’s Genome & Company that is devoted to microbiome anticancer drug development, declared plans to build a US$125 million plant in the United States together with List Labs, to engage in the commercial production of new microbiome therapeutics.22 Early in 2023, South Korean start-up LISCure Biosciences Inc. also announced a multi-year collaboration with Celltrion to identify novel microbiome therapy for Parkinson’s disease.23
Challenges to Overcome
Despite these optimistic trends, bringing LBPs to the market is no easy feat. Firstly, the exact mechanisms behind the therapeutic effects of LBPs are not fully elucidated due to our limited knowledge of the rules governing the assembly of microbial communities and the unique nature of each person’s microbiome.24 These factors present a great obstacle to developing optimised treatments and understanding the potential long-term risks associated with LBPs.
Furthermore, translating research results into commercial therapies is hindered by the sheer number of variables that need to be considered when developing and prescribing LBPs. These variables include the dose formulation and species traits of microbial candidates; the density, diversity, and community structure of the residential bacteria; and the age, immune system, and genetics of the host, all of which may vary greatly between microbes and between patients.
Finally, there are gaps in the parameters and regulatory approval process for LBPs that have yet to be addressed. Since LBPs are living organisms, storage conditions and manufacturing processes can heavily influence their properties. Consequently, it is challenging to compare results between studies and to develop consistent regulatory standards. In addition, some LBPs may be categorised as either probiotic or drug, or both. If considered as drugs, the question of whether they can be approved based on the process and requirements established for conventional biologics arises. Developers of LBPs are also faced with intellectual property and patent protection challenges since existing laws prohibit live organisms and naturally occurring materials from being patented.25
What’s Next for LBPs? Recommendations and Outlook
Evidently, much remains to be discovered, discussed, and validated. To gain a deeper and more comprehensive understanding of LBPs, databases and tools of molecular biology need to be expanded, made more affordable and accessible. Regulatory guidelines for the standardisation of engineered bacterial therapeutics also need to be established.
Nevertheless, the outlook of LBPs appears promising. Once scientists demonstrate favourable safety profiles, determine convenient routes of administration, identify broad combinations of therapeutic effectors, and realise scalable manufacturing, we may expect the emergence of living medicines that circumvent the risks posed by traditional drugs and pave the way to a new era of next-generation drug discovery and development.
- Gilbert, J. A., & Neufeld, J. D. (2014). Life in a World without Microbes. PLoS Biology, 12(12), e1002020. https://doi.org/10.1371/journal.pbio.1002020
- Gupta, A., Singh, V., & Mani, I. (2022). Dysbiosis of human microbiome and infectious diseases. Progress in Molecular Biology and Translational Science, 192(1), 33–51. https://doi.org/10.1016/bs.pmbts.2022.06.016
- Voth, E., & Khanna, S. (2020). The Integrative Human microbiome project: a mile stone in the understanding of the gut microbiome. Expert Review of Gastroenterology & Hepatology, 14(8), 639–642. https://doi.org/10.1080/17474124.2020.1780912
- Landsdowne, L.E. (2022). Live Biotherapeutics ‒ A Novel Way To Treat Disease. Technology Works Drug Discovery. https://www.technologynetworks.com/drug-discovery/blog/live-biotherapeutics-a-novel-way-to-treat-disease-360566
- Barra, M., Danino, T., & Garrido, D. (2020). Engineered Probiotics for Detection and Treatment of Inflammatory Intestinal Diseases. Frontiers in Bioengineering and Biotechnology, 8. https://doi.org/10.3389/fbioe.2020.00265
- Ağagündüz, D., Gençer Bingöl, F., Çelik, E., Cemali, Ö., Özenir, Ç., Özoğul, F., & Capasso, R. (2022). Recent developments in the probiotics as live biotherapeutic products (LBPs) as modulators of gut brain axis related neurological conditions. Journal of Translational Medicine, 20, 460. https://doi.org/10.1186/s12967-022-03609-y
- Moodley, T., & Mistry, E. (2019). Could the Gut Microbiome Revolutionize Medical Care? Current Status and Initial Considerations for Successful Development and Commercialization of Microbiome Therapies. Syneos Health. https://www.syneoshealth.com/insights-hub/can-the-gut-microbiome-revolutionize-medical-care
- S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. (2016). Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Early-Clinical-Trials-With-Live-Biotherapeutic-Products–Chemistry–Manufacturing–and-Control-Information–Guidance-for-Industry.pdf
- Charbonneau, M. R., Isabella, V. M., Li, N., & Kurtz, C. B. (2020). Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nature Communications, 11, 1738. https://doi.org/10.1038/s41467-020-15508-1
- Claesen, J., & Fischbach, M. A. (2014). Synthetic Microbes As Drug Delivery Systems. ACS Synthetic Biology, 4(4), 358–364. https://doi.org/10.1021/sb500258b
- Cao, F., Jin, L., Gao, Y., Ding, Y., Wen, H., Qian, Z., Zhang, C., Hong, L., Yang, H., Zhang, J., Tong, Z., Wang, W., Chen, X., & Mao, Z. (2023). Artificial-enzymes-armed Bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis. Nature Nanotechnology. https://doi.org/10.1038/s41565-023-01346-x
- Takeda, T., Asaoka, D., Nojiri, S., Yanagisawa, N., Nishizaki, Y., Osada, T., Koido, S., Nagahara, A., Katsumata, N., Odamaki, T., Xiao, J.-Z., Ohkusa, T., & Sato, N. (2022). Usefulness of Bifidobacterium longum BB536 in Elderly Individuals With Chronic Constipation: A Randomized Controlled Trial. American Journal of Gastroenterology, 118(3), 561–568). https://doi.org/10.14309/ajg.0000000000002028
- Lim, J. (2022). Zhiyi Biotech Finishes Series B Funding With $45 Million For Live Biotherapeutics. Gene Online. https://www.geneonline.com/zhiyi-biotech-finishes-series-b-funding-with-45-million-for-live-biotherapeutics/
- Sun, M., Ye, H., Shi, Q., Xie, J., Yu, X., Ling, H., You, S., He, Z., Qin, B., & Sun, J. (2021). Both‐In‐One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem‐Amplifying Reactive Oxygen Species‐Immunity Responses. Advanced Healthcare Materials,10(21), 2100950. https://doi.org/10.1002/adhm.202100950
- Ho, C. L., Tan, H. Q., Chua, K. J., Kang, A., Lim, K. H., Ling, K. L., Yew, W. S., Lee, Y. S., Thiery, J. P., & Chang, M. W. (2018). Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention. Nature Biomedical Engineering, 2(1), 27–37. https://doi.org/10.1038/s41551-017-0181-y
- Li, R., Helbig, L., Fu, J., Bian, X., Herrmann, J., Baumann, M., Stewart, A. F., Müller, R., Li, A., Zips, D., & Zhang, Y. (2019). Expressing cytotoxic compounds in Escherichia coli Nissle 1917 for tumor-targeting therapy. Research in Microbiology, 170(2), 74–79. https://doi.org/10.1016/j.resmic.2018.11.001
- Chen, Z., Guo, L., Zhang, Y., L. Walzem, R., Pendergast, J. S., Printz, R. L., Morris, L. C., Matafonova, E., Stien, X., Kang, L., Coulon, D., McGuinness, O. P., Niswender, K. D., & Davies, S. S. (2014). Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. Journal of Clinical Investigation, 124(8), 3391–3406. https://doi.org/10.1172/jci72517
- Hsieh, P.-S., Ho, H.-H., Hsieh, S.-H., Kuo, Y.-W., Tseng, H.-Y., Kao, H.-F., & Wang, J.-Y. (2020). Lactobacillus salivarius AP-32 and Lactobacillus reuteri GL-104 decrease glycemic levels and attenuate diabetes-mediated liver and kidney injury in db/db mice. BMJ Open Diabetes Research & Care, 8(1), e001028. https://doi.org/10.1136/bmjdrc-2019-001028
- Somabhai, C. A., Raghuvanshi, R., & Nareshkumar, G. (2016). Genetically Engineered Escherichia coli Nissle 1917 Synbiotics Reduce Metabolic Effects Induced by Chronic Consumption of Dietary Fructose. PLoS ONE, 11(10), e0164860. https://doi.org/10.1371/journal.pone.0164860
- Chaudhary, G. (2022). The live biotherapeutic products and microbiome manufacturing market is projected to grow at a CAGR of 20% during 2022-2035, claims Roots Analysis. Roots Analysis. https://www.globenewswire.com/en/news-release/2022/04/06/2417921/0/en/The-live-biotherapeutic-products-and-microbiome-manufacturing-market-is-projected-to-grow-at-a-CAGR-of-20-during-2022-2035-claims-Roots-Analysis.html
- Holobiome Acquires Microbiome Startup AsiaBiome. (2022) Microbiome Times. https://www.microbiometimes.com/holobiome-acquires-microbiome-startup-asiabiome/
- Keenan, J. (2021). List Bio to build new $125M microbiome plant in Indiana, hire 210. Fierce Pharma. https://www.fiercepharma.com/manufacturing/list-bio-to-build-new-125m-microbiome-plant-indiana-hire-210
- Korean firms to develop novel microbiome treatment for Parkinson’s disease. (2023). BioSpectrum Asia Edition.
- Ducarmon, Q. R., Kuijper, E. J., & Olle, B. (2021). Opportunities and Challenges in Development of Live Biotherapeutic Products to Fight Infections. The Journal of Infectious diseases, 223(12 Suppl 2), S283–S289. https://doi.org/10.1093/infdis/jiaa779
- Bamforth, M. (2019). Supporting Commercialization of Live Biotherapeutic Products for Microbiome-Based Therapies. Pharma’s Alamanac. https://www.pharmasalmanac.com/articles/supporting-commercialization-of-live-biotherapeutic-products-for-microbiome-based-therapies