Equaly: Unlocking the Therapeutic Potential of the Innate Immune System

Even though innate immunity was considered to be an antigen-independent system for fighting pathogens, Jean-Marie Saint-Remy discovered that one of the major components of innate immunity, natural killer T (NKT) cells, can be activated by protein antigens. 

“All of the sudden you have a possibility to interfere with the immune system in the good sense of the word—interfere with an antigen-specific for let's say an infection, a tumor, and so on, without the risk of off-target effects,” says Saint-Remy, founder and chief scientific officer of Equaly, a startup based in Belgium.

With a portfolio of patent applications, he established Equaly in 2016 to develop a platform that could use his discovery to harness the innate immune system against a range of disorders. By specifically modulating the innate immune system without the risk of off-target effects, Equaly aims to pioneer novel, cost-effective curative approaches to cure diseases instead of simply alleviating their symptoms, or increasing life expectancy. 

Equaly’s platform is based on a new NKT cell lineage. Most NKT lineages, or variants, are activated by lipids or glycolipids, says Saint-Remy. “The lineage we have identified is activated by peptides, amino acid stretches, hydrophobic peptides, as a matter of fact.”

A number of key characteristics of peptide-specific NKT cells makes them preferred targets for therapeutic applications: (1) the peripheral repertoire is not purged from its auto-reactivity (similar to MAIT cells); (2) the class I MHC-like restriction element, CD1d, is non-polymorphic; (3) NKT cells carry an effector memory phenotype; (4) activated NKT cells produce a large array of cytokines, chemokines, and effectors such as granzymes and perforin, creating a virtuous circle of activation of class I and class II-restricted T cells, NK cells, as well as M2 to M1 transformation. 

Equaly has identified in the peripheral blood mononuclear cells of healthy people from the ages of 30 to 75, the presence of NKT cells with cytotoxic properties, recognizing epitopes from mutated transcription factors associated with cancer, including p53. 

“Let's imagine, for instance, ovarian cancer where 95 percent of the patients have a mutation of TP53. p53 peptides are presented by CD1d at tumor cell surface, and NKT cells capable of being activated by those mutated peptides are present in peripheral blood,” says Saint-Remy. “So, after NKT cell activation, or passive transfer of NKT cells, the synapse created at tumor cell surface generates the production of a number of factors leading to cytotoxicity against the tumor cell. The peripheral blood repertoire of NKT cells being unrestricted, you can indeed find NKT cells against mutated transcription factors associated with cancer. More than half of human cancers have TP53 mutations in the DNA binding site. So, the tools are there.” 

Saint-Remy says all Equaly has to do is identify the peptide that is presented and activating NKT cells and make it, for example, as a vaccine for peripheral tissue administration. 

“The field of innate immunity is really exploding and I think we have a card to play here because of the vast specificity of this population of NKT cells,” says Saint-Remy. “And another thing is that the restriction factor, CD1d, which is presented at the surface of the antigen-presenting cell, is not polymorphic, which means the risk of triggering an allo-reaction against what you use is close to nothing. That's a very big advantage. Because of this lack of CD1d polymorphism, you can take the engineered NKT of interest, expand them in vitro, and when you have identified a patient with the corresponding mutation, you just go within minutes with an NKT administration without worrying about the possibility of an allo-reaction, what we call an ‘off-the-shelf’ therapy.”

Equaly is currently working on creating a vaccination strategy for TP53 mutations, which are associated with 60 percent of human cancers. The strategy is two-fold: first, test whether the cancer cell expresses CD1d, and if it doesn’t, force it to do so with clinically-applicable agents such as retinoic acid, rapamycin, or epigenetic regulators; and second, produce a panel of peptides corresponding to the mutation to elicit an NKT population specific to the epitopes, based on what is presented by the tumor cell. 

“Basically, our first therapeutic target is oncology, including p53 and BCL2 in follicular lymphoma and p53 in ovarian cancer,” Saint-Remy says. However, a similar strategy is applicable to “situations such as intracellular infections, viral infections in particular.” 

It is also possible to adapt the strategy to autoimmune diseases, such as type 1 diabetes or multiple sclerosis, by eliciting NKT cells that recognize CD1d+ antigen-presenting cells expressing autoantigen epitopes associated with the autoimmune reaction. 

On the other hand, Saint-Remy also notes that Equaly has identified the mechanism leading to immunogenicity of IV-administered replacement factors used in gene defect diseases. Antigen-specific NKT cells are activated immediately after replacement factor administration and these cells represent an obligate intermediate towards adaptative immunity and elicitation of specific antibodies.

 “So, what we do is identifying, within the amino acid sequence of replacement factors, stretches of amino acid activating specific NKT cells, and eliminate their capacity to be presented by CD1d by introducing a few amino acid substitutions.” Full proof of concept has been obtained for some replacement factors and work is in progress to render AAV vectors non-immunogenic.   

Finally, Equaly has another ace up its sleeve—cost efficiencies of its therapies because of the ease of manufacturing them. If you go for a vaccination, you need a peptide of about 20 amino acids, costing about €10 per patient, says Saint-Remy. You can use the same peptide for whoever has the same mutated transcription factor.  To provide an example, for mutations of the DNA binding site of p53, a series of ± 20 peptides might be sufficient. 

Once you know exactly what the patient has in terms of mutation, you just go to your shelf, take the peptide of interest and make the vaccine, Saint-Remy says. “The same applies for NKT cell passive administration. Population of NKT cells corresponding to p53 mutations are easily expanded in vitro and stay ready for administration without the pain and the cost associated to modify them, such as for CAR-T cells.”

Located on the campus of the University of Louvain, Equaly has links with its Oncology Institute, and with the de Duve Institute in Brussels. The startup had a first financing of about €4 million that went toward its work on replacement factors and more recently another €3 million toward developing a cancer vaccine. A California-based Institute has marked its interest for the technology, as well as several VCs. Equaly is actively seeking investors and collaborators and joined Bioneex to facilitate its efforts. 

Partnering with patient organizations is also a priority and Equaly actively encourages them to get in touch with the company. As its name signifies, Equaly aims to develop therapies accessible to everyone. 

A doctor with a degree in internal medicine, Saint-Remy has been working on immunotherapy for 30 years.  “I can tell you that if I can cure one patient one day,” he says, “I would be the happiest man in the world. The rest is of no importance to me.”