NEW YORK – Following last year’s €75 million ($79.2 million) Series A round of financing, Paris-based cell therapy company Mnemo Therapeutics is exploring the "grey genome" of transposable elements (TEs) for highly tumor-specific cancer therapy targets.
The four-year-old company published a study earlier this month in Cell Reports, in which it identified 370 such TE-encoded and human leukocyte antigen (HLA) I-bound peptides expressed only or mainly in glioblastoma cancer cells.
Mnemo has now patented "multiple" such TE-derived and cancer-associated peptides, as well as the discovery process for finding them, with the goal of identifying possible therapeutic targets for further development.
TEs, also known as transposons, are mobile elements of DNA that "jump" from one area of a chromosome to another. Studies estimate that roughly 45 percent of human DNA derives from TEs, although these are mainly noncoding sequencing.
Several studies have detailed how epigenetically reactivated TEs can promote numerous oncogenic pathways by serving as cryptic promoters for genes that would be otherwise silenced in healthy cells.
"Preventing TE derepression at the epigenetic level might be a general strategy to [inhibit] many of their deleterious effects," she added, "including the generation of TE-derived peptides," said Julia Fuchs, a group leader at the Center for Interdisciplinary Research in Biology at Paris' Collège de France.
While published research into the oncogenic effects of TEs focuses largely on the downstream events that Fuchs describes, Mnemo chose to look further upstream.
"[Mnemo's] original insight," said François Gaudet, the company's CSO, "was that in cancer where splicing is dysregulated, maybe some of these sequences become part of mature transcripts. Then if they're translated, you get neoantigens potentially on the [cell] surface."
By this hypothesis, TEs link to exon sequences, essentially forming fusion proteins, whose peptides the cell can then display on its surface.
In addition to finding the TE-derived peptides on glioblastoma cell surfaces, Mnemo determined that these elicited an immunogenic response from T cells in vitro. The company expects that this immunogenicity and specificity to glioblastoma makes them potential therapeutic targets.
In vitro results do not always translate to in vivo settings, however, as the biological environment of the latter is orders of magnitude more complex.
To that end, Mnemo has been conducting further studies in-house, as it generates data with an eye toward future publications.
Gaudet said that the company has so far detected TE-derived peptides on the surfaces of cancer cell lines and has shown that synthetic peptides built from these sequences and loaded onto major histocompatibility complexes trigger immunogenic responses from patient-derived T cells.
The TE-derived peptides that Mnemo has so far discovered come from the company's proprietary EnfiniT target identification and T cell engineering platform, a proprietary end-to-end process for identifying therapeutic peptide targets.
The platform consists of both public and proprietary RNA and mass spectrometry databases that are used to identify sequences such as those bridging TEs and exons, from which protein structure can be predicted.
"Then with a lot of bioinformatics works," Gaudet said, "you try to predict what [that] would look like as a protein, if it were to be translated."
Gaudet declined to describe this bioinformatics work in greater detail, referring to it as the firm's "secret sauce."
Mnemo's strategy places it on a rather small playing field.
Argonaut, founded by former Genentech bioinformatics scientist Haiyin Chen-Harris, is another company pursuing a similar strategy, though.
Chen-Harris and her colleagues published a study in Nature Communications positing that tumor-specific TE reactivation might augment immunotherapy. The company, however, remains at too early a stage of development to comment on its technology or plans.
Other companies, such as San Diego-based Poseida Therapeutics, use TEs as vectors to deliver therapeutic transgenes to cells.
Among other projects, Mnemo is also working on an HLA-independent TCR, or HIT, designed to remain functionally persistent in T cells and to have greater antigen sensitivity than other TCRs. The company published a preliminary study characterizing HIT receptors in Nature Medicine earlier this year.
Interestingly, epigenetic reactivation of TEs appears to grow more frequent as one ages and may affect other pathological conditions beyond cancer.
"It would certainly be worth exploring whether TE-derived peptides are synthesized in the brain following TE derepression with age and could somehow play a role in neuroinflammation, a hallmark of neurodegenerative diseases," Fuchs said.
Mnemo has so far raised close to $100 million and employs approximately 70 people, distributed across its three locations in Paris, New York City, and Princeton, New Jersey.
The company is planning a Series B round for sometime either later this year or early next year, depending on market factors.
"The market is kind of up and down right now," said CEO Robert LaCaze. "But we're in pretty good shape for our cash burn."