Our lead asset, VTX-001, is a monoclonal antibody that targets integrin avβ8 and has shown single-agent activity in multiple preclinical cancer models, demonstrating promising efficacy and superior potency compared to other known TGF-β inhibitors- all with a clean safety profile.
In the last seven years, immunotherapies have revolutionized cancer care. Most promisingly, patients who do respond show long and durable remission from cancer. Unfortunately to date those therapies have worked in only 10-20% of cancer patients, and there is an urgent need to develop novel immunotherapies that will expand those benefits to the other 80-90% of patients by effectively targeting a broader range of cancers, as well as increasing the efficacy of existing therapies. The primary reason patients fail to respond is due to an immunosuppressive response that limits the benefits of current immunotherapies also known as checkpoint inhibitors.
Integrin-mediated activation of TGF-β is at the root of resistance to therapies in the cancer tumor micro-environment, fibrosis, and NASH. Integrins are vital components of the cell’s machinery to link the intracellular and extracellular environment and essential aspects of cell behavior. Studies have demonstrated their connection with several types of cancer, particularly during metastases and angiogenesis (Marelli et al., 2013). Integrins represent cell surface receptors and are in an ideal position to become pharmacological targets.
A primary factor in the limitation of immunotherapy efficacy and patient benefit is cytokine TGF-β. TGF-β has long been known to be a central node in driving immune suppression, limiting the effectiveness of checkpoint inhibitors. In cancer, TGF-β is a key driver of tumor proliferation, inflammation, invasion and metastasis, angiogenesis, and avoidance of immune surveillance. Various attempts have been made to therapeutically drug this target by blocking active TGF-β released from its latent complex. These attempts have shown limited but promising efficacy, and have been hampered by safety issues, most critically cardiac toxicity.
In preclinical trials, our lead asset, VTX-001 has been shown to successfully stop activation of TGF-β by integrin αvβ8, a primary source of cancer immunosuppression across a broad spectrum of cancers, including lung cancer, the leading cause of all cancer deaths in both men and women, estimated at 23% and 22% for 2020, respectively. Integrin αvβ8 expression has been found in multiple tumor types, is correlated with poor survival, and is independent of PD-1(Programmed cell death protein 1). Targeting integrin αvβ8 does not affect TGF-β2, the blockage of which has historically been associated with adverse events.
Venn’s preclinical assets and integrin portfolio successfully address both these challenges.
OUR INTEGRIN PORTFOLIO
The reason for VTX-001’s superior potency and safety was detailed in a January 2020 groundbreaking paper by Venn Scientific Advisory Board Member, Dr. Stephen Nishimura, published in the prestigious, peer-reviewed scientific journal Cell. Dr. Nishimura’s paper showed that TGF-β is activated in its latent form in the tumor microenvironment, as opposed to the classical models that require the release of soluble TGF-β in its active form before it can be targeted. Dr. Nishimura’s pioneering discovery has the potential to enable immuno-oncology therapies to markedly expand the universe of previously unresponsive tumors. (Campbell et al., Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β, Cell (2020), https://doi.org/10.1016/j.cell.2019.12.030).
The integrin αvβ8 structure was characterized for the very first time in 2018 by the inventors of VTX-001, including Dr. Nishimura, one of the paper’s senior authors, and the results were published in the international scientific journal Nature Structural & Molecular Biology (Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension). Venn’s lead asset, VTX-001, is a monoclonal antibody that selectively targets integrin αvβ8 and has shown single-agent activity in multiple preclinical cancer models.
Of critical importance, VTX-001 has been shown to safely target TGF-β1 and TGF-β3 and completely avoid blocking TGF-β2. The blockage of TGF-β2 is associated with cardiac toxicity, a harmful complication of many existing cancer therapies.
In preclinical trials, Venn’s lead asset VTX-001 has been shown to successfully stop activation of TGF-β by integrin αvβ8, a primary source of cancer immunosuppression across a broad spectrum of cancers, including lung cancer, the leading cause of all cancer deaths in both men and women, estimated at 23% and 22% for 2020, respectively.
Venn’s proprietary diagnostic, VTX-001DX, detects the expression of αvβ8 in human cells and will be used in later-stage clinical trials to enrich the patient selection, thereby selecting patients most likely to benefit from VTX-001.
In addition to VTX-001, Venn’s integrin portfolio includes two other first-in-class monoclonal antibodies under development targeting integrins:
VTX-002, a potent, humanized monoclonal antibody that targets both αvβ8 and αvβ6 for fibrotic diseases
VTX-003, a monoclonal antibody currently in discovery that targets integrin αvβ1 for liver fibrosis and NASH
PUBLICATIONS AND POSTERS
January 16, 2020
National Center for Biotechnology Information
October 18, 2018
Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
Nature Structural and Molecular Biology
July 30, 2018