DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity

Ewa Cendrowicz, Lisa Jacob, Shirley Greenwald, Ami Tamir, Iris Pecker, Rinat Tabakman, Lucy Ghantous, Liat Tamir, Roy Kahn, Jasmine Avichzer, Alexandra Aronin, Shira Amsili, Elina Zorde-Khvalevsky, Yosi Gozlan, Martijn Vlaming, Gerwin Huls, Tom van Meerten, Michal Elhalel Dranitzki, Adam Foley-Comer, Yaron PeregAmnon Peled, Ayelet Chajut*, Edwin Bremer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: Treatment of Diffuse Large B Cell Lymphoma (DLBCL) patients with rituximab and the CHOP treatment regimen is associated with frequent intrinsic and acquired resistance. However, treatment with a CD47 monoclonal antibody in combination with rituximab yielded high objective response rates in patients with relapsed/refractory DLBCL in a phase I trial. Here, we report on a new bispecific and fully human fusion protein comprising the extracellular domains of SIRPα and 4-1BBL, termed DSP107, for the treatment of DLBCL. DSP107 blocks the CD47:SIRPα ‘don’t eat me’ signaling axis on phagocytes and promotes innate anticancer immunity. At the same time, CD47-specific binding of DSP107 enables activation of the costimulatory receptor 4-1BB on activated T cells, thereby, augmenting anticancer T cell immunity. Methods: Using macrophages, polymorphonuclear neutrophils (PMNs), and T cells of healthy donors and DLBCL patients, DSP107-mediated reactivation of immune cells against B cell lymphoma cell lines and primary patient-derived blasts was studied with phagocytosis assays, T cell activation and cytotoxicity assays. DSP107 anticancer activity was further evaluated in a DLBCL xenograft mouse model and safety was evaluated in cynomolgus monkey. Results: Treatment with DSP107 alone or in combination with rituximab significantly increased macrophage- and PMN-mediated phagocytosis and trogocytosis, respectively, of DLBCL cell lines and primary patient-derived blasts. Further, prolonged treatment of in vitro macrophage/cancer cell co-cultures with DSP107 and rituximab decreased cancer cell number by up to 85%. DSP107 treatment activated 4-1BB-mediated costimulatory signaling by HT1080.4-1BB reporter cells, which was strictly dependent on the SIRPα-mediated binding of DSP107 to CD47. In mixed cultures with CD47-expressing cancer cells, DSP107 augmented T cell cytotoxicity in vitro in an effector-to-target ratio-dependent manner. In mice with established SUDHL6 xenografts, the treatment with human PBMCs and DSP107 strongly reduced tumor size compared to treatment with PBMCs alone and increased the number of tumor-infiltrated T cells. Finally, DSP107 had an excellent safety profile in cynomolgus monkeys. Conclusions: DSP107 effectively (re)activated innate and adaptive anticancer immune responses and may be of therapeutic use alone and in combination with rituximab for the treatment of DLBCL patients.

Original languageAmerican English
Article number97
JournalJournal of Experimental and Clinical Cancer Research
Volume41
Issue number1
DOIs
StatePublished - 14 Mar 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • 4-1BB
  • B cell lymphoma
  • CD47-SIRPα ‘don’t eat me’ signaling
  • Phagocytosis
  • T cell co-stimulation

Fingerprint

Dive into the research topics of 'DSP107 combines inhibition of CD47/SIRPα axis with activation of 4-1BB to trigger anticancer immunity'. Together they form a unique fingerprint.

Cite this