Step Pharma is developing a novel class of oral drugs that specifically inhibit the enzyme cytidine triphosphate synthase 1 (CTPS1).

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 strongly supports the concept that inhibition of CTPS1 represents a potential novel therapeutic approach for oncology and autoimmune conditions.


DNA and RNA synthesis are essential metabolic processes and intracellular nucleotide levels are regulated by two pathways: salvage & de novo. The final rate limiting step is the conversion of UTP to CTP. Unlike other steps in the pathway there are two enzymes that can catalyze this reaction – CTP Synthase 1 (CTPS1) and CTPS2.

An efficient immune response triggered by antigen recognition results in a rapid and intense cell division of T lymphocytes, and therefore metabolic adaptation. Proliferation in response to antigen receptor-mediated activation is defective in CTPS1-deficient T and B lymphocytes. Thus CTPS1 plays 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.

Human genetics has demonstrated that CTPS1 has an essential and non-redundant role in lymphocyte proliferation. CTPS2 has a broad tissue expression profile and is unable to complement for the lack of CTPS1. Patients carrying the CTPS1Δ18 mutation have no phenotype on other tissues.

Selective inhibition of CTPS1 (avoiding CTPS2) thus represents an ideal target for inhibition of T cell proliferation. CTPS1 could be the Achilles heel for T-cell proliferation.

Taken from “When lymphocytes run out of steam - Veillette, A & Davidson, D. (2014) Nature, volume 510, pages 222-223 DOI:(10.1038/nature13346)

a, In normal lymphocytes (T and B cells), stimulation of the cells’ antigen receptor triggers a series of molecular changes that induce the cells to proliferate, fuelling the immune response. These events include an increase in levels of the enzyme CTPS1 and its product, CTP, which supports the increased DNA synthesis required for cell proliferation.

b, In lymphocytes from CTPS1-deficient humans, stimulation by antigen results in some, but not all, of the molecular changes associated with lymphocyte activation. In particular, there is no increase in CTP levels in the activated cells, resulting in compromised DNA synthesis, reduced lymphocyte proliferation and an impaired immune response.


Lymphoma is the most common blood cancer and has two main forms Hodgkin Lymphoma (HL) and non-Hodgkin Lymphoma (NHL). These occur when T or B lymphocytes grow and multiply uncontrollably. Cancerous lymphocytes can travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood or other organs and form a tumour.

The peripheral T cell lymphomas refers to more than eight different lymphomas and account for 4% of all patients diagnosed with NHL. Each is classified as a rare disease with the most common being peripheral T cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T cell lymphoma (AITL), adult T cell leukemia/lymphoma (ATLL) and cutaneous T cell lymphoma (CTCL).

The B cell lymphomas are also sub-divided into different conditions. Follicular lymphoma (FL) is the most common indolent (slow growing) form of NHL accounting for approximately 12% of all B cell NHLs. Mantle Cell Lymphoma is a more aggressive B cell lymphoma that accounts for approximately 2% of all B cell NHLs. The disease originates in the mantle zone of the lymph node hence the name.

T-cell malignancies have been neglected over the past decade and there is a critical need for new therapies. Outcomes with standard frontline chemotherapy are poor and the 5 year survival rates remain below 30%. Approved second line agents show limited efficacy and many patients relapse or become refractory to current drugs. Current clinical trials are primarily focused on combinations with approved agents.

CTPS1 has been shown to be critical for T and B cell proliferation in response to immune challenge and this same pathway seems to be activated to support the uncontrolled growth of cancerous T and B cells. Inhibiting CTPS1 thus represents an alternative targeted approach to block proliferation and induce cell killing of cancerous T and B cells in lymphoma.

A novel CTPS1 inhibitor could be immediately adopted as 2nd line and ultimately become 1st line in combination regimens.

Cell‐of‐Origin Schema for the Major Mature T‐Cell Lymphoma Subtypes. − indicates negative; +, positive; ALK, anaplastic lymphoma kinase; γ,δ‐MTCL, γδ mature T‐cell neoplasm; γ,δ‐T, γδ T‐cell lymphoma; MTCL, mature T‐cell neoplasm; NOS, not otherwise specified; Th1, T‐helper 1 cells; Thf, follicular helper CD4 T cells; Treg, regulatory T cells.

Autoimmune Disease

Autoimmune Disease is caused when the normal control mechanisms of the human immune system break down, resulting in immune attack on the body’s cells and tissues leading to a wide range of disease pathologies.

Autoimmune Diseases include Autoimmune Myopathies, Crohn’s Disease, Graft-Versus Host Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Psoriasis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Systemic Sclerosis, Sjorgren’s Syndrome, Type 1 Diabetes, among others. These diseases can start early and last a lifetime, resulting in decades of suffering and disability.

Proliferation of activated lymphocytes is a normal component of the immune reaction towards pathogens, but in autoimmune and inflammatory diseases the proliferation of activated lymphocytes is deleterious. Accordingly, several classes of immunosuppressive agents have been developed to inhibit and control these excessive and pathological responses but any have broad and non-specific effects that limit their efficacy and use.

More recent treatments acting specifically on a particular mediator of the disease (e.g. cytokines) have shown more limited side effects but leave a high proportion of non-responding patients without a therapeutic solution. There is therefore a great need for novel safe and effective treatments for Autoimmune Diseases.

A goal in the development of new drugs for auto-immune diseases is to look for agents with novel mechanisms of action that provide specific modulation of the immune system rather than global immunosuppression. Step Pharma’s CTPS1 inhibitors have the potential to achieve selective modulation of activated lymphocytes.

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