Demcizumab (Anti-DLL4/Notch Pathway)

Proposed Mechanism of Action

Demcizumab (OMP-21M18) is a humanized monoclonal antibody directed against Delta-like ligand 4 (DLL4), a key mediator of Notch signaling. In preclinical studies, binding of demcizumab disrupts the interaction between DLL4 and the Notch receptors, thus inactivating Notch signaling.1

Preclinical studies demonstrated that, compared with controls, demcizumab decreased tumor growth, delayed tumor recurrence after chemotherapeutic treatment, and decreased the proportion of cancer stem cells.2  DLL4 blockade on endothelial cells may induce non-productive vascularization, leading to tumor growth inhibition.3 More recent preclinical research has shown that anti-DLL4 appears to act on the regulation of T cells through IL-17 and the suppression of monocytic myeloid-derived suppressor cells (MDSCs).4

CSC, cancer stem cell; DC, dendritic cell; DLL4, Delta-like ligand 4; IL, interleukin; i-NOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; Th17, T helper 17.

Demcizumab by Disease State

Demcizumab in Lung Cancer

Rationale for Clinical Development

Celgene has partnered with OncoMed Pharmaceuticals in developing demcizumab for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). In in vitro studies, demcizumab exhibited activity against a number of solid tumor types.1,2,4,5

Demcizumab in Pancreatic Cancer

Celgene has partnered with OncoMed Pharmaceuticals in developing demcizumab for the treatment of pancreatic cancer. In in vitro studies, demcizumab has exhibited activity against a number of solid tumor types.3,4 In a preclinical pancreatic cancer study, inhibition of DLL4 demonstrated anti-tumor activity and decreased cancer stem cell number.1

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Demcizumab is an anti-DLL4 antibody currently owned by OncoMed Pharmaceuticals. Demcizumab is currently being tested in combination with carboplatin and pemetrexed in a phase II trial of patients with nonsquamous NSCLC.

References

  1. Yen WC, et al. Clin Cancer Res. 2012;18:5374-5386.
  2. Hoey T, et al. Cell Stem Cell. 2009;5:168-177.
  3. Hicklin D. Nature Biotechnol. 2007;25:300-302.
  4. Srivastava M, et al. Poster at AACR 2015. [abstract 225].
  5. Fischer M, et al. Cancer Res. 2011;71:1520-1525.