Cry5B consortium for soil-transmitted helminths
  • Awarded Year
    2015
  • Awarded Amount
    $1,002,996
  • Disease
    NTDs Soil-transmitted helminthiasis (roundwor
  • Intervention
    Drug
  • Development Stage
    Lead Optimization
  • Collaboration Partners
    Ajinomoto Co., Inc., Meiji Seika Pharma Co., Ltd., University of Massachusetts Medical School, PATH

Introduction and Background of the Project

Introduction

Soil-transmitted helminthiasis (STH) infections are considered among the most pressing of global health problems, thought to parasitize some 2 billion people worldwide, with the heaviest burden placed on the poorest and most deprived communities. STH can cause infant mortality, but their greatest impact is thought to come as a result of morbidity associated with anemia and malnutrition. The World Health Organization (WHO) estimates that in 2013, over 368 million schoolchildren were treated with anthelmintics in endemic countries but this is only 42% of all children at risk. In 2010, the total impact of STH was estimated at 5 million disability-adjusted life-years.

 

Project objective

The high-level objective of this project is to attempt the development of the Cry5B protein as a new treatment for soil-transmitted helminths (STH). Cry5B is a powerful, naturally occurring anthelmintic protein from the bacteria Bacillus thuringiensis (Bt) that could improve the treatment of STH and their management through mass drug administration (MDA) campaigns. In animal models of STH infections, both purified Cry5B protein and cell lysates enriched for crystals have shown potency against several intestinal nematodes in vitro that is 100-fold greater than albendazole, one of the current drug treatments, on a molar basis. Cry5B protein is not systemically absorbed when administered orally and is likely to be safe, as are other Bt crystal proteins like those expressed in commercialized Bt crop plants. The proposed work in this project will have the following three objectives:

1) Develop appropriate microbial strains to express Cry5B protein

2) Develop fermentation processes for growing Cry5B protein-expressing strains.

3) Explore processes for the purification of Cry5B protein from the production strains.

 

Project design

Each of the collaboration partners brings a unique capability to this project. PATH is the leader in global health innovation. An international nonprofit organization, PATH saves lives and improves health, especially among women and children. PATH brings our entrepreneurial insight, scientific and public health expertise, and passion for health equity to this project, as well as over 40 years of experience in working with partners on global health issues. Ajinomoto Co. is a global manufacturer of high-quality seasonings, processed foods, beverages, amino acids, pharmaceuticals and specialty chemicals. For many decades Ajinomoto Co. has contributed to food culture and human health through wide-ranging application of amino acid technologies. Since its commercialization of monosodium glutamate (which confers the umami taste) in 1908, Ajinomoto has been a pioneer in fermentation technology and the production of amino acids and other biological products. Meiji Seika Pharma Co., Ltd. (MSP) handles businesses in specialty and generic pharmaceuticals, agricultural chemicals and veterinary drugs. Since starting penicillin production in 1946, MSP has had extensive experience in the development and manufacturing of finished formulations and active pharmaceutical ingredients for pharmaceutical products, pesticides, veterinary medicines, and industrial enzymes by using microorganisms. Dr. Raffi Aroian of the University of Massachusetts Medical School (UMMS) is a leading expert in the Cry5B protein. Dr. Aroian and his laboratory at UMMS were the first to characterize Cry5B and its mechanism of action. From the beginning, Dr. Aroian has championed the potential of Cry5B as a new anthelmintic that could have a significant impact on the management of the global STH problem. He and his laboratory have established the animal models required to test the efficacy of Cry5B and combinations thereof against a number of parasitic nematodes. His laboratory has made the first attempts at expressing Cry5B in other bacteria and has all the necessary reagents and tools to work with Cry5B.

 

MSP and a contractor will attempt Cry5B protein production in two additional proprietary microbial expression systems. Dr. Aroian and his laboratory at UMMS will analyze Cry5B samples produced by Ajinomoto and MSP to verify its anthelmintic activity.

How can your partnership (project) address global health challenges?

The drugs currently used to treat STH infections were introduced from the veterinary pharmacopeia and no new drugs have been introduced in more than 30 years. The drugs most widely used in mass drug administration campaigns against STH (the benzimidazoles albendazole and mebendazole) are threatened by the rise of resistance, which has already rendered some nicotinic agents, such as levamisole, largely ineffective in the treatment of livestock with parasitic nematodes. A significant gap in the profile of all of the currently approved anthelmintic drugs is that they are contraindicated for women in their first trimester of pregnancy, which leaves the mother and her fetus vulnerable to the effects of STH-induced anemia and malnutrition, and out of reach of a therapeutic intervention. Cry5B would be a great addition to the therapeutic options for managing of STH infections for the following reasons:

 

1) In the model nematode C. elegans, the activity of Cry5B is not affected by resistance to existing agents (benzimidazoles and nicotinic agents).

2) Cry5B can form part of a combination therapy with existing drugs. It acts synergistically with some nicotinic agents and resistance to these can make STH hypersensitive to Cry5B.

3) As a non-absorbed protein product that binds to a target known only in invertebrates, Cry5B is expected to be safe for all patients, including pregnant women and young children.

4) If Cry5B can be expressed at high levels in a probiotic strain of Bacillus, it may be possible to create a product with both anthelmintic and probiotic benefits.

What sort of innovation are you bringing in your project?

Cry5B is a completely novel anthelmintic with a unique mechanism of action that is unaffected by resistance to existing drugs. As a non-absorbed therapeutic agent, it is also likely to have an excellent safety profile. However, as a protein product, its production on a commercial scale also presents a unique challenge.

 

To increase our chances of overcoming this challenge, we are taking a multi-pronged strategy that involves a variety of approaches: traditional methods of strain improvement and optimization of fermentation conditions, as well as more sophisticated methods involving heterologous recombinant microbial expression systems.

 

Role and Responsibility of Each Partner

Ajinomoto Co. is a global manufacturer of high-quality seasonings, processed foods, beverages, amino acids, pharmaceuticals and specialty chemicals. For many decades Ajinomoto Co. has contributed to food culture and human health through wide-ranging application of amino acid technologies. Since its commercialization of monosodium glutamate (which confers the umami taste) in 1908, Ajinomoto has been a pioneer in fermentation technology and the production of amino acids and other biological products. Meiji Seika Pharma Co., Ltd. (MSP) handles businesses in specialty and generic pharmaceuticals, agricultural chemicals and veterinary drugs. Since starting penicillin production in 1946, MSP has had extensive experience in the development and manufacturing of finished formulations and active pharmaceutical ingredients for pharmaceutical products, pesticides, veterinary medicines, and industrial enzymes by using microorganisms. PATH is the leader in global health innovation. An international nonprofit organization, PATH saves lives and improves health, especially among women and children. PATH brings our entrepreneurial insight, scientific and public health expertise, and passion for health equity to this project, as well as over 40 years of experience in working with partners on global health issues. Dr. Raffi Aroian of the University of Massachusetts Medical School (UMMS) is a leading expert in the Cry5B protein. Dr. Aroian and his laboratory at UMMS were the first to characterize Cry5B and its mechanism of action. From the beginning, Dr. Aroian has championed the potential of Cry5B as a new anthelmintic that could have a significant impact on the management of the global STH problem. He and his laboratory have established the animal models required to test the efficacy of Cry5B and combinations thereof against a number of parasitic nematodes. His laboratory has made the first attempts at expressing Cry5B in other bacteria and has all the necessary reagents and tools to work with Cry5B.