NP137-Lead asset

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Netrin-1 as an actionable target for the treatment of cancer

Netrin-1 is extensively known for its role during embryonic development (1). Netrin-1 has been described as a ligand for the prototypical dependence receptors DCC and UNC5B (2). DCC and UNC5B have been shown to have dual signaling depending on netrin-1 availability (3): in the presence of netrin-1, these receptors induce various intracellular signal including an Epithelial-to-Mesenchymal Transition (EMT) (4), in the absence of ligand, they activity trigger cell death (5). Experimental genetic silencing of DCC pro-death activity or genetic gain of netrin-1 in adult mice leads to tumoral progression (6-7).

Netrin-1 is up-regulated in the vast majority of human cancer

It was shown that netrin-1 is gained in the vast majority of human cancer as a pro-tumoral mechanism.

Cancer Type Autocrine Secretion or Over-expression of Netrin-1
Melanoma 80%
Glioblastoma 77%
Ovarian Cancers 76%
Pancreatic Adenocarcinoma 61%
Metastatic Breast Cancers 60%
Sarcoma > 50%
Non-Hodgkin Lymphomas > 50%
NSCLC 47%
Neuroblastoma 38%
Gastric Cancer, IBD related tumors 21%
Gastric Cancer, CRC sporadic tumors 7%
Prostate Cancer Aggressiveness

Netrin-1 titration is associated with tumor growth inhibition

Experimental silencing or titration of netrin-1 is associated with tumor growth inhibition in various preclinical models.

NP137 is a first-in-class, first-in-human, humanized monoclonal antibody of IGg1 isotype directed against netrin-1

NP137 was engineered to specifically and efficiently bind to netrin-1 and to inhibit the interaction ligand/receptor.

NP137 is alleviating resistance to chemotherapies and immune checkpoint inhibitors by modulating phenotypic plasticity

Because netrin-1 is both a survival factor and an inducer of EMT, disrupting netrin-1 with NP137 is associated with both tumor growth inhibition and EMT inhibition. Because EMT is a natural break for the efficacy of chemotherapies and immune-checkpoint inhibitors, NP137 was shown in preclinical model to potentiate the anti-tumor activity of both chemotherapies and immune-checkpoint inhibitors.

NP137 is a safe product currently assessed in several phase II trials

NP137 confirmed its excellence safety profile during the clinical Phase I monotherapy, while presenting early signs of clinical activity with objective responses and disease stabilization. These signs of clinical activity, together with the confirmation of the reversion of tumoral EMT in patients treated with NP137, have led to conduct the ambitious GYNET phase 2 trial assessing NP137 in combination with carbotaxol and/or pembrolizumab in patients with endometrial and cervix cancer.

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NETRIS Pharma’s clinical development plan

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