Community Research and Development Information Service - CORDIS

FP7

HERMIONE-2MAN Report Summary

Project ID: 601716
Funded under: FP7-HEALTH
Country: France

Final Report Summary - HERMIONE-2MAN (First in Man Novel Anticancer Therapeutic based on Dependence Receptors Concept)

Executive Summary:
It is usually assumed that transmembrane receptors are inactive unless bound by their respective ligand. The coordinatoor has shown that some receptors dubbed as dependence receptors are not inactive in the absence of their respective ligands but actively trigger apoptosis. Thus, dependence receptors (DR) expressed at the cell surface lead the cell to be dependent for its survival on ligand availability. The FP6 HERMIONE project (2006-2009) aimed to show that DRs are negative regulators of tumor progression and to provide a setting in which DRs could be used in therapeutic perspective. Of interest, during the course of HERMIONE, it was shown that in a large fraction of human cancers, netrin-1 is autocrinally expressed to block DCC/UNC5H-induced apoptosis and that interference with netrin-1/receptors interaction is associated with tumor growth and metastasis inhibition in various animal models of cancer. The results of HERMIONE and subsequent R&D performed by the HERMIONE-spin-off company Netris Pharma (NP) allowed the development of promising anti-cancer drug candidates: antibodies blocking the interaction between netrin-1 and its DRs (anti-netrin-1 mAb).
The HERMIONE-2MAN project allowed the characterization and production of a very appealing netrin-1 mAb, blocking the interaction between netrin-1 and its DR receptor UNC5B. After humanization and optimization, the mAb named NP137 has been manufactured by Polymun, and validated. Pharmacodynamic properties and pharmacology were explored and ability of this antibody to show anti-tumor effect in various animal models was demonstrated used either in monotherapy or in combination with conventional treatments.
This anti-cancer drug candidate has shown an original mode of action where it could control tumor cell stemness by blocking the netrin-1-dependent cross-talk between tumor cells and their supporting microenvironment. Results from both GLP-compliant repeated-dose toxicity studies conducted in mice and cynomolgus monkeys indicate that it induced no toxic effects relevant to humans and is well tolerated. It is now ready to be used in the first-in-man-first-in-class phase I clinical trial that was prepared during the project.

Project Context and Objectives:
It is usually assumed that transmembrane receptors are inactive unless bound by their respective ligand. Against this dogma, the CLB proposed that some receptors may also be active in the absence of ligand and in this case trigger cell death. These receptors were called dependence receptors (DR) as their expression at the cell surface leads the cell to be dependent for its survival on ligand availability. The prototypic DRs are receptors DCC and UNC5H that bind their ligand netrin-1. The FP6 HERMIONE project (2006-2009) aimed to show DRs are negative regulators of tumor progression and to provide a setting in which DRs could be used in therapeutic perspective. Of interest, during the course of HERMIONE, it was shown that in a large fraction of human cancers netrin-1 is autocrinally expressed to block DCC/UNC5H-induced apoptosis and that interference with netrin-1/receptors interaction is associated with tumor growth and metastasis inhibition in animal models of various cancer types. The results of HERMIONE and subsequent R&D performed by the HERMIONE-spin-off company Netris Pharma (NP) allowed the development of promising anti-cancer drug candidates: antibodies blocking the interaction between netrin-1 and its DRs (anti-netrin-1 mAb). The objective of the HERMIONE-2MAN project was thus to take the most promising anti-netrin-1 mAb into human early clinical trial with the help of a private partner specialized in antibody manufacturing (POLYMUN) and with two clinical entities CLB and EORTC.
Project Results:
The HERMIONE-2MAN project allowed the characterization and production of a unique netrin-1 mAb, which was obtained after mice immunisation, humanization and further optimization. This antibody is the only netrin-1 mAb described to date to inhibit the interaction between netrin-1 and the main death driver receptor UNC5H2/B. Based on the X-ray netrin-1 structure identification, the consortium was able to show that this antibody named NP137 is binding to the V-2 domain of netrin-1, which is the region where UNC5B is interacting with netrin-1.
A master cell bank was designed to produce NP137 and Polymun developed the complete production process (upstream, downstream, analytical methods) necessary for the GMP production of antibody based on two appropriate technologies for optimizing the antibody production and deliver a clinical batch.
The initial batches of antibody have been released to CLB and NP to explore pharmacodynamic properties of this candidate drug and pharmacology. The work undergone during the project allowed the preclinical proof of concept for the development of NP137 and highlights its great developability. Results from both GLP-compliant repeated-dose toxicity studies conducted in mice and cynomolgus monkeys indicate that NP137 induced no toxic effects relevant to humans and show that NP137 therapy is well tolerated. Moreover pharmacokinetic analysis revealed that NP137 has a strong profile with a half-life of 9-11 days in cynomolgus monkeys.
Regarding pharmacology, the first in vivo experiments have provided further demonstration of the anti-tumor activity of NP137 and more specifically in settings of combination either with conventional chemotherapies or with epidrugs (Grandin et al., 2016, Cancer Cell; Grandin et al., 2016, EMBO MM). Moreover the in vivo preclinical data brings evidence supporting a specific effect of NP137 on the so-called Cancer Stem Cells. Indeed, the consortium recently observed that netrin-1 pathway is acting as a key modulator of normal stem cell pluripotency and reprogramming (Ozmadenci et al., 2016, Nat Comm) and thus we have shown that NP137 is actually controling tumor cell stemness by blocking a netrin-1-dependent cross-talk between tumor cells and their supporting microenvironment. These preclinical data suggested that NP137 may clinically be efficient on progression free survival by elimination the cancer cells which are involved in clinical progression.
Taken together, the original mode of action, the positive half-life and the absence of toxicity in animal models led the consortium to fill in a clinical trial application in June 28th 2016 with the hope to be able to include the first patient in what is going to be a first-in-man-first-in-class clinical trial.

Potential Impact:
Main dissemination activities and exploitation of results
The results of the Hermione-2Man project have been presented over the program duration through posters in oncology focused events:
- American Association for Cancer Research annual meeting (2015);
- 4th Lyon Comprehensive Cancer Research Center Meeting (2016).
Three publications related to the Hermione-2Man project have also been submitted to peer-reviewed journals and accepted:
- Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance (Nature Communication, 2015)
- Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference (EMBO Molecular Medicine, 2016);
- Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers (Cancer Cell, 2016).
One more publication currently in preparation will describe the preclinical specification –pharmacokinetics, toxicity, pharmacology- of NP137 to Clinical Research Cancer.
Finally, 4 patents were filed for by Netris Pharma.
Knowledge gathered during the project on the mechanism of action of anti Netrin1 mAb will be used for further research work.

Impact on patients and their quality of life
HERMIONE-2MAN provides a new targeted anti-cancer drug and we hope will have a wide impact on health and quality of life. Indeed, the cancers in which netrin-1 is up-regulated are among the commonest forms of diagnosed cancer and are among those with a crucial unmet medical need, both in Europe and around the world. By providing insight on the molecular events that lead to the onset and evolution of diseases affecting large numbers, HERMIONE-2MAN has a clear vocation to impact the quality of lives of millions. Current anti-cancer conventional treatments are highly toxic to normal tissue and cause substantial loss of life quality. By specifically targeting the interaction of DRs and their ligand, HERMIONE-2MAN will provide a targeted therapeutic strategy, reducing the side effects and therefore improving the overall well-being of the treated patients. Of key importance, the results of our project will represent the stepping-stone of an all variety of new anti-cancer drugs targeting a so far uncovered pathway. Indeed, even though netrin-1 is the most-advanced target and anti-Netrin-1 mAb the most advanced compound, the observation that not only netrin-1 but other ligands are up-regulated to block apoptosis induced by other DRs in a variety of cancer type, will lead to the development by the same consortium of different mAbs possibly efficient in an even larger spectrum of patients with cancers.

Impact on public health
As it was shown that combined treatment based on conventional chemotherapies (CT) and netrin-1 interference could be associated with increased therapeutic effect, the use of anti-Netrin-1 mAb could help reducing the dosage of CT treatments. Thanks to this new drug, a significant reduction of healthcare expenditure is expected due to a decrease in the use/dosage of CT as well as a decrease in the number of clinical visits and additional treatments due to CT side-effects. A major issue of targeted therapies in cancer appears to be the rapid development of mechanism of resistance that often arises and possibly limits the effect of targeted treatment to gain a few months of increased survival. One first way to circumvent resistance is to propose a cocktail of mAbs targeting different ligands of different DRs and CLB has shown that the same tumor can show up-regulation of different ligands of different DRs supporting the view that developing a anti-Netrin-1 antibody and subsequently developing other mAbs targeting other ligands of other DRs should allow to move from one resistance to another and increase substantially survival. Another way to circumvent resistant is to kill tumor initiating cells (that are often more resistant to classic chemotherapies and proliferation-based targeted therapies - e.g. kinase inhibitors). Interestingly, preliminary data from CLB have shown that tumor initiating cells from different type of cancer appear to up-regulated netrin-1 in a higher magnitude than the tumor bulk. This observation, that needs to be further demonstrated and pursued in animal models, may support the view that an anti-Netrin-1 mAbs could be effective in killing tumor initiating cells and may consequently have a longer impact on patient survival.

Scientific impacts
The DR notion was initially proposed by D.E Bredesen and P. Mehlen mainly thanks to in vitro experiments. This notion, that has acquired more and more interest among scientists is now being formally demonstrated in vivo (see the back-to-back Nature manuscripts[M. Castets et al., 2012, Nature, 482:534-7] P.Krimpenfort et al., 2012,Nature, 482:538-41]) but is still challenged by others who do not accept that a transmembrane receptor may be active in the absence of its ligand. The demonstration of gain of survival of patients showing up-regulation of ligand of DRs would be a definitive demonstration of the scientific importance of this cell biology paradigm.

Impact on European biotechnology research
Opening a brand new therapeutic option against cancer is not so common. Reinforcing the pioneering research in the DR concept, originated from a European laboratory, may open the way to additional European research to strengthen the leading position of Europe in the field of DR. In particular, Europe should invest in such internally-born concept in order to help bridging the gap with the US biotechnology sector. Moreover, this project will have a key impact on the two SMEs implicated in the project. POLYMUN will gain knowledge all over Europe as the CRO implicated in the development of a successful mAbs with commercial outcome. NP will become a clinical biotec and the leading pharma developing drugs based on the dependence receptor paradigm with possibly wide impact reinforcing the pharmaceutical leadership in Europe.

Impact on SMEs
NETRIS Pharma (NP) and its founders aim at exploiting the full potential of dependence receptors as novel and powerful targets against several types of cancers. NP will initially focus on the anti-Netrin-1 mAb, which will also serve as a demonstrator and a door opener for the development of drugs against other dependence receptor targets, developing innovative products that will be a benefit to patients, and will appeal to health agencies, to payers, to physicians and to the pharmaceutical industry. The HERMIONE-2MAN project will allow NP to demonstrate the interest and potential of this new therapeutic avenue. Taking advantage of its pioneering position, NP intends to become the worldwide leader in targeted therapies for the treatment of cancer based on the innovative apoptosis pathway of the DRs.
As already started, NP will continue to develop new drug candidates on other DRs pathways (so far 4 NP patents cover the targeting of 4 other ligands of DRs up-regulated in cancer). NP’s medium term goal is to optimize these leads into clinical candidates and push them into clinical trials, to take full advantage of and reinforce its leadership position in the field. This additional research will be funded with the venture capital investment that has been secured by NP, complemented by the upfront and milestones that NP expects to be able to draw from the success of its mAb funded through HERMIONE-2MAN.
Afterwards, NETRIS Pharma will progressively expand into a larger product portfolio, targeting other dependence receptors, for the treatments of other cancer indications. NP will seek to become a partner of choice of specialized contractors and large pharmaceutical companies, where collaborations will be set-up to carry on the development, the registration and the commercialization of therapeutic products.
As a summary, thanks to the HERMIONE-2MAN project, NP will be soon in a position to out license its first lead candidate. In both cases, in-licensing revenues will provide the financial basis to take other DR programs into clinical trials and towards the market. Patentable results related to the development of the anti-Netrin-1 mAb are owned in majority by Netris Pharma.
In a long term view, NP sees itself as:
- a research-based pharmaceutical company specialized in and with world-leadership in the DR field;
- having the in-house capacities to develop clinical candidates and taking them through early-stage clinical trials in the order of magnitude of 150 FTEs;
- a company that would be profitable being funded by the upfront, milestone and royalty payments from its development and distribution partners; eventually by public markets through an IPO (Initial Public Offering) (markets permitting).

POLYMUN will make use of its proprietary non-exclusive mAb production process (BEST) and accumulate its know-how to be used for further commercial protein production for customers and own R&D projects. The potential for improving the efficiency of recombinant protein by a factor of two has a current market value of 4 billion USD per year, with the majority still being antibodies. This project will serve as reference project in order to attract the attention of the pharmaceutical industry. In addition, POLYMUN will be manufacturer for later clinical phases and market supply of this antibody in case of successful clinical outcome, creating long term revenues for POLYMUN. In this case, POLYMUN’s turnover would be increased as an average contract production for repeated batch would be around 1 Million Euro. POLYMUN will also be chosen as an obvious partner for the production of the NP pipeline mAbs.
In the current plan of POLYMUN, the HERMIONE-2MAN project is the first project using the BEST technology. In parallel to this project, POLYMUN will try to attract new customers such as biotech start-ups and pharmaceutical companies with this improved technology. It should enable POLYMUN to stay competitive as CMO. POLYMUN is aiming to increase its sales in the field of biopharmaceutical contract manufacturing in the next 5 years by 75%. With the BEST technology, we will target the following groups of customers and users: biotech start-ups, academic groups, other pharmaceutical companies. POLYMUN envision having its first customer using the BEST technology within the next year. This will depend if POLYMUN can convince a potential customer to apply the technology without a reference product with clinical application. The outlook to apply the technology in the HERMIONE-2MAN project should be very supportive and reduce the time to market of this new technology. A first contract was signed in August 2015 with an Austrian biotech start-up to apply the BEST technology for cell lines development. Moreover, the HERMIONE-2MAN project offers to POLYMUN the opportunity to: (a) Increase sales in case of additional productions; (b) Increase efficiencies thanks to the higher productivity of the cell lines with the BEST technology; (c) Improve Customer Service, with potential shorter development time for cell lines with the BEST technology.

List of Websites:
http://www.hermione2man.eu

Centre Léon Bérard (CLB) : Patrick MEHLEN patrick.mehlen@lyon.unicancer.fr
Netris Pharma (NP) : Jordan GUYON jordanguyon@netrispharma.com
Polymun Scientific Immunobiologische Forschung (POLYMUN) : Dietmar KATINGER Dietmar.Katinger@polymun.com
European Organisation for Research and Treatment of Cancer (EORTC) : Stéphane LEJEUNE stephane.lejeune@eortc.be

Contact

Marina ROUSSEAU-TSANGARIS
Tel.: +33 04 78 78 26 18
Fax: +33 4 78 78 29 55
E-mail

Subjects

Life Sciences
Record Number: 192743 / Last updated on: 2016-12-14
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