Background Dual signalling protein 107 (DSP107) is a trimeric fusion protein consisting of the extracellular domains of human SIRPα and 4-1BBL. SIRPα binds to CD47, frequently overexpressed on cancer cells, and 41BBL binds to 41BB on activated T-cells. The SIRPα domain triggers the innate immune response by inhibiting the CD47/SIRPα ‘don’t eat me’ signalling. It thus promotes phagocytosis of cancer cells by granulocytes, macrophages and dendritic cells. With its other side, 41BBL domain binds to pre-activated T cells and stimulates their expansion, cytokine production and cytolytic effector function. Our hypothesis is that augmented phagocytosis and improved co-localization of immune cells will lead to better antigen presentation towards activated T and B cells and the generation of memory T and B cells will be enforced. As result DSP107 might lead to immunity after rechallenge with the same tumour type.
Materials and Methods Primary phagocytes were incubated with stained tumour cells in presence or absence of DSP107 or/and therapeutic antibodies. Fluorescence microscopy measured uptake of tumour cells by macrophages. FACS identified primary granulocytes positive for CD11b staining and membrane dye. HT1080-41BB cells were mixed with HT1080-CD47 or HT1080-wt in presence of DSP107 and IL-8 release to supernatant was measured by ELISA. Further, primary T cells were co-cultured with αCD3Fc and fluorescent protein transduced carcinoma cells at different DSP107 concentrations.
Results The number of granulocytes that phagocyte tumour cells was increased in presence of DSP107. Further, DSP107 not only stimulated more macrophages to engulf tumour cells, but also the number of tumour cells that were taken up per phagocyte rose. Already enhanced phagocytosis of tumour cells by therapeutic antibodies (e.g. Cetuximab, Rituximab and Trastuzumab) was improved even further by DSP107. A model system showed that activation of the 41BB/41BBL axis by DSP107 was dependent on cross-linking via CD47 domain. This indicates low off-target T cell activation. Apart from the model system, DSP107 stimulated primary T cells in co-culture with carcinoma cells (transduced to express αCD3 and a fluorescent protein). Cytolytic activity against carcinoma cells was improved and outgrowth of tumour cells was reduced in a dose dependant manner.
Conclusions DSP107 blocks the CD47/SIRPα checkpoint resulting in enhanced tumour cell phagocytosis and stimulates the 41BB/41BBL axis leading to T cell mediated tumour cell killing. DSP107 is a novel bifunctional therapeutic that targets and activates both innate and adaptive anticancer immune responses. DSP107 is a first-in-class drug candidate that can be used as a monotherapy or in combination with tumor-targeting monoclonal antibodies to trigger induction of anti-cancer immunity. DSP107 is currently tested in IND-enabling studies and clinical development is planned to commence in 2020.
Disclosure Information E. Cendrowicz: None. L.J. Jacob: A. Employment (full or part-time); Significant; KAHR Medical. S. Greenwald: A. Employment (full or part-time); Significant; KAHR Medical. G. Huls: None. M. Dranitzki-Elhalel: None. Y. Pereg: A. Employment (full or part-time); Significant; KAHR Medical. A. Chajut: A. Employment (full or part-time); Significant; KAHR Medical. E. Bremer: None.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.