Step Pharma is developing a novel class of oral nucleotide synthesis inhibitors targeting CTPS1 (cytidine triphosphate synthase 1) to induce selective modulation of specific immune cell populations such as T and B cells, translating to better efficacy and an improved therapeutic index. The discovery of CTPS1 as a potential target for immunomodulation was based on studies of humans with a CTPS1 deficiency. CTPS1 inhibitors could be used to treat auto-immune diseases and also lymphoproliferative cancers.

A mutation of the CTPS1 gene – identified in 8 children by Dr. Peter Arkwright (University of Manchester) and the team of Dr. Sylvain Latour and Pr. Fischer at Imagine Institute (Paris, France) – causes a novel immunodeficiency characterized by an impaired capacity of activated lymphocytes to proliferate, without affecting non-hematopoietic cells (Martin et al., Nature. 2014 Jun 12;510(7504):288-92). This finding validates the CTPS1 target in humans.

An efficient immune response triggered by antigen recognition results in a rapid and intense cell division of T lymphocytes, and therefore metabolic adaptation. Cytidine nucleotide triphosphate (CTP) is a precursor required for DNA synthesis, a crucial step in cell division. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases 1 and 2 (CTPS1 and CTPS2). Proliferation in response to antigen receptor-mediated activation is defective in CTPS1-deficient T (and B) lymphocytes. In contrast, proximal and distal TCR signalling events and responses are only weakly affected by the absence of CTPS1. The CTP concentration is low in activated CTPS1-deficient cells. Importantly, CTPS1 expression was found to be low in all tissues tested including resting T cells, but rapidly and strongly up-regulated following TCR activation. In contrast, CTPS2 was found to be moderately increased after TCR activation. This is the first time that CTPS1 was shown to play a key and specific role in the immune system by its capacity to sustain the proliferation and the expansion of activated T lymphocytes during the immune response.

Importantly, CTPS1-deficient patients only exihibit certain immunodeficiencies without other clinical problems strongly suggesting a predominant and key role of CTPS1 in selected immune cell populations. CTPS1 therefore represents a therapeutic target for a new class of highly selective immunomodulatory drugs.

There is also a long established practice to use nucleotide synthesis inhibitors (e.g. leflunomide, azathioprine, mycophenolic acid) as treatment for autoimmune disease, but their dosing is limited due to their lack of tissue selectivity. This further validates CTPS1 as a promising target for autoimmune diseases.