Blue Bees Therapeutics: boosting immune cells to treat cancer

From the Department for Medicines and Health Technologies (MTS - Univ. Paris-Saclay, Alternative Energies and Atomic Energy Commission CEA, National Research Institute for Agriculture, Food and the Environment INRAE), the biotech Blue Bees Therapeutics is offering a new immunotherapy strategy to fight tumours. Housed at CEA Paris-Saclay, it hopes to bring its drug candidate BB-100, based on the patented i-Ther technology, into Phase I/II clinical trials as early as 2025.

The story of the start-up Blue Bees Therapeutics began in 2020. "That year, I met Michel Léonetti, a research engineer at the CEA and the project's scientific lead. He was looking for someone who could help him develop a structure," recalls Philippe Berthon, CEO of the start-up. Working with Nabil Gharios, managing partner at Auriga Partners, a venture capital management company, the two men approached the CEA and the Technology Transfer Acceleration Company (SATT) Paris-Saclay. SATT Paris-Saclay granted them over than €600,000 in subsidies. In March 2022, Blue Bees Therapeutics was launched. In July of the same year, it obtained the support of the French public investment bank, BPI France and won the i-Lab competition, which awarded it €375,000. And the support continued to pour in. In August 2022, Blue Bees Therapeutics completed its first round of financing with business angels, raising €218,000.

Strong support

The start-up Blue Bees Therapeutics has been able to launch due to the confidence demonstrated by the CEA and its supporters, in particular BPI France and the SATT Paris-Saclay. "With their cooperation, we could create a story to appeal to investors. Without SATT Paris-Saclay, we would not be where we are today and France, generally, has provided us with immense support. It has an ecosystem that is very favourable for developing start-ups. What's happening in France right now is spectacular," says Philippe Berthon. He continues: "We have secured close to €1.5 million in equity, which will allow us to build a team and deploy our first drug candidate, BB-100 and our immunotherapy discovery platform i-Ther. We currently have three employees, housed at CEA Paris-Saclay, but we will probably recruit one or two more during the year. We are also going to contact start-up incubators so we have other structures on the Orsay campus of Université Paris-Saclay." Not stopping there, Blue Bees Therapeutics will launch a new €10 million round of financing in April 2023 to finance human clinical trials for its first drug candidate, BB-100, which uses the patented i-Ther technology.

i-Ther, an anti-immune checkpoint technology

I-Ther is a technology that enables the creation of new treatments belonging to the family of so-called "anti-immune checkpoint" immunotherapies. Instead of attacking tumour cells directly, these therapies target the immune system with the goal of restoring or improving its function so that it can fight tumour expansion more effectively. First appearing in the 2000s and awarded a Nobel Prize in Medicine in 2018 for the individuals who discovered them, immunology researchers James Allison and Tasuku Honjo, they dramatically increase survival rates in patients by 10% to 40%. "Many start-ups and big pharma companies are currently in a race to discover innovative immunotherapeutics. We are part of this race by developing our technology, which helps to activate certain immune system cells more effectively," explains Michel Léonetti of the Immunoanalysis Studies and Research Laboratory (LERI), part of the Pharmacology and Immunoanalysis Service (SPI) of the MTS department.

Anti-immune checkpoint immunotherapies target proteins that act as immune checkpoints or ICPs. These immune checkpoints are triggered when proteins on the surface of immune cells (especially T cells) bind to partner proteins on other cells. In some cases, the trigger sends an inhibitory signal to the T cell, which can no longer eliminate the tumour cells. As Michel Léonetti explains, "the injection of anti-ICP antibodies prevents the interaction between the two proteins and therefore removes the inhibition of the T cell."
 
Treatments derived from I-Ther technology fall into this "anti-immune checkpoint" category. However, unlike the immunotherapies currently used for patients, which directly attack the immunosuppressed T cells, they work further upstream in the immune response process. This is because they target and activate dendritic cells, other immune system cells, which contribute to the activation of T cells. "Because we operate further upstream in the immune process, our drugs are potentially complementary to those used today. In addition, since dendritic cells are present in all patients, our treatments would be operable in all cancer cases, even in patients who do not respond to conventional immunotherapies," explains Michel Léonetti.

 
BB-100, an immunotherapeutic drug candidate

Based on the I-Ther technology, the biotech Blue Bees Therapeutics is developing a first drug candidate, named BB-100. "This is a monoclonal antibody fragment combined with a ligand of heparan sulfate proteoglycan (HSPG). BB-100 therefore has two cell interaction functions. The antibody fragment will bind to the receptor expressed by the dendritic cell and the ligand to HSPG. This double interaction results in an increase in cellular activation," says Michel Léonetti.

BB-100 is produced recombinantly using HEK 293 cells, human embryonic kidney cells, which are traditionally used in antibody production. Various purification stages follow. "For the time being, we prefer to administer the drug subcutaneously, which has the advantage of being faster than infusion. Ideally, patients should be able to inject themselves on a weekly basis," adds the research engineer.

A potential market launch in 2035

At this time, the BB-100 drug candidate is still in animal testing. "We are currently in non-regulatory preclinical studies. We characterise the purity of BB-100 and its biological properties in in vitro models, notably in human cells, and in vivo in animals. In animals, the tumour cells are injected into mice and then BB-100 is inoculated to see if it slows down the tumour growth," explains Michel Léonetti.

Upon completion of these analyses, the drug candidate will enter regulatory preclinical development. According to Philippe Berthon, "This stage will last about two years and will cost us between six and seven million euros. By the end of 2026, BB-100 will enter Phase I/II clinical trials." This phase is used to study tolerance to the drug and to define the recommended dose and frequency of administration. Tests are performed on a small number of patients, between 10 and 40. In 2028, the drug will move into Phase II for two to three years. The objective is to confirm its clinical and/or pharmacological activity at the recommended dose. "If the results of Phase II are positive, we could sell the company to a big pharma able to carry out Phase III studies and to proceed with the marketing of the drug," explains Philippe Berthon.

Reference:
Patent "Immunomodulatory complex and uses thereof for therapy", WO2021239996 - 02/12/2021; FR2005663 - 28/05/2020