Advances in CAR-T cell therapy have carved a path for improved treatments in the field of oncology, in particular haematological cancers. In 2018, the European Medicine's Agency approved the first two CAR-T cell therapies, Kymriah® and Yescarta®, for marketing authorisation for the treatment of certain cancers 1. Since then, CAR-T cell therapy has been rolled out across Europe, largely for the treatment of large B-cell lymphoma, mantle cell lymphoma, and acute lymphoblastic leukaemia. However, the same success has not been realised for solid tumours 2.
To address the challenge of cell therapy for the treatment of solid tumours, many have looked towards the power of natural killer (NK) cells as a potential therapy. In particular, CAR-NK cell therapy is thought to have several advantages over CAR-T cell therapy, such as an improved safety profile with a reduced risk of cytokine release syndrome and lower incidence of graft versus host disease 3. CAR-NK cells may also provide the much needed improved efficacy in treating solid tumours. It is believed that CAR-NK cells may be able to overcome tumour escape problems as seen with CAR-T cells due to their retention of antigen-independent activity even when there is loss of antigen dependent killing 4.
As advancements in the NK cell therapy area are gaining speed, so is the complexity of the IP landscape. International and European patent filings mentioning NK cell therapy have been rising sharply over the last 5 years (Fig.1), with a number of large players in the game. Gilead Sciences Incorporated and Novartis AG have strong patent portfolios in this area (Fig. 2), each with over 200 applications pending and 25-50 granted patents that at least mention NK cell therapy in the text of the applications. The University of Texas MD Anderson Cancer Center also hold a number of pending and granted patents directed towards methods of producing CAR-NK cells and claims towards therapeutic compositions of NK cells with engineered receptors.
Figure 1: Total number of International and European patent filings since 2011.
Figure 2: Top 25 assignees with European or International patent applications mentioning NK cell therapy in the text.
To further strengthen their patent portfolios, a number of high profile collaborations and deals have been struck. Gilead have partnered with Dragonfly Therapeutics to further strengthen their patent portfolio and to gain access to the 5T4-targeting investigational immunotherapy program and, upon completion of certain preclinical activities, a licence to use Dragonfly's TriNKET" technology to develop and commercialise NK cell engagers. Dragonfly Therapeutics have further capitalised on their IP position by licencing multiple NK cell therapy candidates to Merck and Bristol Myers Squibb, in the fields of oncology and neuroinflammation.
MD Anderson have partnered with Takeda to develop off the shelf NK cell products and, more recently, have granted exclusive licences to the Norwegian company, Zelluna Immunotherapy, to expand their offering of off the shelf TCR-NK cells for the treatment of cancer 5. Under the agreement with MD Anderson, Zelluna will have exclusive rights to develop and commercialise certain TCR-NK products. These TCR-NK products include allogeneic cellular therapies that combine the inherent killing mechanism and the allogeneic nature of NK cells with the antigen-specific targeting capabilities of TCRs.
As evidenced by Dragonfly's IP position for their NK cell platform technology and MD Anderson's position for off the shelf NK cell therapies, valuable gains can be made by having a solid and well thought out IP position. As this field grows, the already crowded IP landscape will continue to expand and become more challenging to navigate for companies wishing to expand in the field and to get their products to market.
However, despite the rapid rise in patent filings in Europe, relatively few patents have been granted. This adds to the complexity of the patent landscape, as those wishing to develop their products in this area will have to continually monitor the progress of these patent applications until grant or make licencing decisions before the scope of the patents and their jurisdictions are clear. One approach to strengthen one's IP position, is to develop a robust patent portfolio for particular NK cell products or methods of manufacture in the European market and seek to cross licencing where possible.
One example of a European company making strides in this area is ONK Therapeutics. ONK, an Irish based company, offer engineered NK cell therapy candidates that express CAR for the treatment of AML, multiple myeloma and a number of solid tumour cancers such as prostate and triple negative breast cancer 6. ONK exclusively in-licence a recently granted European patent from Australia's Walter and Eliza Hall Institute of Medical Research (WEHI) covering CISH knockout NK use in cancer therapy. This licencing deal builds on ONK's already growing patent portfolio on multiple different NK cell checkpoints.
There is clearly competition in this space, therefore a knowledgeable understanding of what competitors and academic institutions are doing is essential. As mentioned above, there is a backlog of pending patent applications in Europe that will proceed to grant over the coming years. This will likely result in a spike in opposition proceedings and litigation action. It is advisable that any organisation wishing to enter into the NK cell therapy market has a freedom to operate assessment performed to avoid any contentious action.
Overall, the advancement of NK cell therapeutics is an exciting development to the cell therapy space, in particular as there is a clear need not being met by CAR-T cells. However, there is much to be considered with respect to patent filing strategy in Europe and beyond but also with respect to freedom to operate and licencing strategies to support NK cell therapies being brought to market. Those that will see success, are those organisations that not only develop the best technology but those who make the right decisions early on with developing their own patent portfolios and striking the best licencing deals.
Footnotes
1. Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries.Jørgensen, J., Hanna, E., & Kefalas, P. 1, s.l. : Journal of Market Access & Health Policy,, 2020, Vol. 8.
2. NHS England. [Online] https://www.england.nhs.uk/cancer/cdf/car-t-therapy/.
3. Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions. Liu, Yan Zhong & Jingfeng. 218, s.l. : Cell Death Discovery , 2024, Vol. 10.
4. Charting a killer course to the solid tumor: strategies to recruit and activate NK cells in the tumor microenvironment. Ana L. Portillo, Jonathan K. Monteiro, Eduardo A. Rojas. 2023.
5. Zelluna Immunotherapy. [Online] [Cited: 23 07 2024.] https://www.zelluna.com/news/exclusive-license-agreements-to-develop-and-commercialize-mage-a4-and-vgll1-targeting-allogeneic-off-the-shelf-tcr-based-natural-killer-tcr-nk-cell-therapies.
6. Labiotech. [Online] [Cited: 23 07 2024.] https://www.labiotech.eu/best-biotech/nk-cell-therapy-companies/.
Originally published by IBI - International Biopharmaceutical Industry Journal
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