With the lucky break of getting the European Medicines Agency (EMA) to relocate post-Brexit from the U.K. to Amsterdam in 2019, The Netherlands is making more noise about its biopharma industry. This nascent sector ranked fourth in GEN’s recent biotech clusters report (behind France, Germany, and the U.K.) and has some real gems with both home-grown and international expertise in its midst.
According to the Dutch Ministry of Economic Affairs’ Communication Channel, Health Holland, The Netherlands has 420 biopharma companies, and these are underpinned by 12 universities engaged in biomedical research and eight university medical centers within a 120-mile radius—making it similar in size to the U.K.’s life science cluster in the Cambridge area. Despite its life science capabilities, The Netherlands has been hiding its light under a bushel until now and is keen to make the most of the golden opportunity the EMA is giving it.
Harnessing the Elite
One promising Dutch biotech, which is developing antibody-based therapies, is AIMM Therapeutics. Spun out of the Academic Medical Center at the University of Amsterdam, the Amsterdam-based firm has been developing therapeutic antibodies since 2004 using a totally different method than most pharma and biotechs.
According to CEO John Womelsdorf, Ph.D., AIMM uses a “contrarian approach” by not screening a vast library looking for monoclonal antibodies (mAbs) that bind to a disease target. “We rely on the human immune system to mount an antibody response against targets of its own choosing. By mining the B cell repertoire of cured cancer patients, so called ‘elite responders,’ AIMM is able to identify human antibodies that bind novel tumor specific targets. Unlike traditional approaches that begin with target selection, AIMM starts with the selection of functional antibodies. These mAbs are then used to identify the tumor target that the patient’s immune system selected. This unbiased approach reveals new vulnerabilities that were exploited by the patient’s immune system, resulting in a cure. It is our belief that such antibodies may be used broadly to treat many patients. All of this is made possible by AIMM’s technology, which is capable of immortalizing the entire B cell repertoire of the elite responder.”
The company originally developed programs that targeted infectious diseases such as CMV, RSV, flu, and MRSA, and have produced antibodies that have advanced to Phase II and, in the case of RSV, a Phase IIb/III pivotal trial, as well as late-stage preclinical development. “Our RSV antibody, MEDI8897 is 100 times more potent than anything on the market and is being developed with MedImmune. This originally came from a kindergarten teacher who was unsurprisingly constantly exposed to RSV via the children, which afforded her strong protection from the virus,” says Dr. Womelsdorf.
The firm is now developing antibodies for oncology indications. Dr. Womelsdorf described one of their lead antibodies, AT1412, commenting, “This antibody was selected from a stage 4 melanoma patient with brain metastasis who was successfully treated with T-cell based immunotherapy, and was still alive and tumor-free after 12 years despite having this aggressive cancer.” He adds, “We screened the B-cells repertoire from this patient using our AIMSelect™ platform and found an antibody that binds to a modified CD9 epitope which you would never see in a traditional screen. This antibody, designated AT1412 was screened against melanoma, colon, lung, and breast cancer cells taken from unrelated donors and showed that this altered CD9 was expressed on all these tumors tested.”
Dr. Womelsdorf has also presented interesting preclinical data on AT1412. The data showed that in mice implanted with a resistant melanoma cell-line, SK-Mel-5, known to be unresponsive to checkpoint inhibitors, continued to grow 28 days after treatment with the anti-PD1 mAb, nivolumab. Whereas tumors treated with AT1412 or AT1412 and nivolumab decreased in size over 28 days. AIMM Therapeutics is continuing to develop AT1412 for melanoma. According to Dr. Womelsdorf, traditional antibodies typically bind targets that are overexpressed on tumor cells but also expressed on healthy tissues, resulting in dose-limiting toxicities and suboptimal therapies. He concludes, “In finding an antibody with such a tumor-specific target like this we have ‘demonstrated a new paradigm in cancer research.’”
Cell Therapy Traction
Dutch biotechs are also building momentum in the cell therapy space, with companies such as Utrecht-based Gadeta taking an alternative approach to developing T-cell based therapies. The firm has developed a technology to engineer alpha beta T cells to express gamma delta T-cell receptors (TCRs). These super-charged T cells are known as TEGs (T cells engineered to express a defined gamma delta TCR).
“Alpha beta T cells are highly cytotoxic and abundant in the blood, but they need expression of cell surface major-histocompatibility-complex (MHC) proteins for target recognition, whereas gamma delta T cells do not require antigen processing and presentation of peptide epitopes. Instead these gamma delta T cells react to molecules produced when cells are stressed to do their job of killing potential tumor cell. However, these are rarer and have a short half-life. Therefore, by replacing alpha beta T-cell receptors with gamma delta TCRs we get T cells that combine the advantages of alpha beta and gamma delta T cells and can, unlike CAR-T cells, (which are mainly alpha beta T cells) target solid tumors,” explains Shelley Margetson, CEO of Gadeta.
The company currently has two T-cell based products in its pipeline: TEG001, which is in a Phase I dose-escalating safety trial to treat Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM), and TEG002 which is in preclinical development.
Both T-cell candidates have a CD277 target which changes conformation, Margetson comments. “When cells are under stress, a pathway is triggered which makes CD277 change its conformation, making the cells visible to our TEGs—it’s like having a pool full of swimmers and being able to see those that are in trouble. Our TEGs only go to those cells that are in difficulty, picks them out, and destroys them,” Margetson adds.
According to Margetson, the ability of TEGs to target solid tumors was the “real trigger” for U.S. cell-therapy firm, Kite Pharma, to enter a strategic partnership with Gadeta in July 2018. Margetson says, “the deal with Kite brings us one of the best-known CAR-T companies to be our big brother.”
Gadeta is now working with HUB (Hubrecht Organoid Technology) on organoids to identify tumors that respond to treatment with its TEG, TEG002, and is looking at improving its cell-therapy production processes. Margetson concludes, “Currently our manufacturing is very manual, but we’re moving over to more automation with the Miltenyi CliniMACS Prodigy® and are beta-testing the Cocoon™ technology from Lonza. This will shorten the production timelines and give us better quality control of our TEGs.”
No strangers to taking risks, the Dutch have built good facilities and companies sometimes from potentially disastrous situations. For example, in 2010 when Merck & Co. closed the Organon research and development facilities at Oss, seventy miles south of Amsterdam, a collaboration between public and private partners created a new life science campus, known as Pivot Park. This includes facilities and infrastructure such as the Pivot Park screening facility, which features an array of robotic drug screening and biological profiling systems and a library of 300,000 drug-like compounds. This and other facilities are available for open-access research, making it attractive for cash-strapped start-ups and growing biopharma companies.
The Dutch have also long been good at forging beneficial international relationships, and Health Holland estimates that 70% of Dutch life science firms have collaborations with foreign companies. Additionally, since most Dutch nationals are bilingual (speaking English and other languages fluently), and the majority of scientific and technical academic courses at their universities are taught in English, The Netherlands is an attractive country for many U.S. and Scandinavian life sciences and biopharma firms to use as a European base. For example, Danish biotech Genmab has had an active R&D site based in Utrecht developing mAbs for oncology indications since 2017. Other firms such as the Janssen Pharmaceutical Companies of Johnson & Johnson and Kite Pharma are also investing in manufacturing infrastructure here, too.
In October 2018, Janssen Vaccines & Prevention opened its new single-use Vaccines Launch Facility in Leiden for producing clinical trial supplies of late-stage vaccine candidates, including its prophylactic HIV vaccine. Here, Janssen’s scientists will utilize a number of platform technologies including Janssen’s PER.C6® cell line, acquired when Johnson & Johnson purchased the Dutch biotech Crucell in 2011. Echoing his belief in the new facility, Dirk Redlich, Ph.D., head of vaccine process and analytical development at Janssen, says, “The bottom line is that we constructed this state-of-the-art center because we have confidence in our ability to deliver transformational vaccines.”
Kite, which already has its European headquarters based in Amsterdam, also has confidence in The Netherlands and plans to open a new 117,000-square-foot facility there for production of its cancer cell therapies. Kite believes its new site at the SEGRO Park Amsterdam Airport in Hoofddorp will enable the company to deliver its cell therapies more efficiently to cancer patients in Europe.
“The Netherlands is such a small country that we have to be outward-facing and work collaboratively with other European countries, as well as those outside the EU, in every industry, not just life sciences,” concludes Victor van Solinge, CEO of Vaxxinova, a veterinary vaccines company. Vaxxinova relocated its international headquarters from Bremen, Germany to Nijmegen in The Netherlands in 2017 for many reasons including the fact that people there could be more multilateral in their approach.
“Since Nijmegen is on the German-Dutch border and our borders are more fluid, we can reach out and benefit from the agri-biotech infrastructure in both countries,” he adds.
While so many other countries are becoming protectionist, perhaps this refreshing “can collaborate” attitude that seems to be ingrained in the Dutch will help The Netherlands to go from strength to strength with its burgeoning biopharma industry.