| Autor: |
Cecile Geuijen, Floris Fransen, Renate den Blanken-Smit, Ton Logtenberg, Vanessa Zondag-van der Zande, Thomas Condamine, Arjen Kramer, Willem Bartelink, Mark Throsby, Pieter Fokko Van Loo, Liang-Chuan Wang, Yao-Bin Liu, Ashwini Kulkarni, Chrysi Kanellopoulou, Rinse Klooster, Simon Plyte, Wilfred E. Marissen, Linda Johanna Aleida Hendriks, Arpita Mondal, Abdul Basmeleh, Shane Harvey, Lex Bakker, Leslie Hall, Jing Zhou, Paul Tacken, Eric Rovers, Hans van der Maaden, Steef Engels, Shaun Stewart, Patrick Mayes, Cheng-Yen Huang, Alla Volgina, Horacio Nastri |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl 3 (2020) |
| ISSN: |
2051-1426 |
| Popis: |
Background MCLA-145 is a CD137 x PD-L1 bispecific antibody that releases PD-L1 mediated T-cell inhibition and activates and expands T cells through agonism of CD137. Immune checkpoint inhibitors (ICI) against PD-(L)1 have demonstrated anti-tumor efficacy in a fraction of patients across a broad range of cancers. CD137 (4-1BB, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor transiently expressed on T cells after TCR engagement. CD137 signaling is triggered by receptor clustering and leads to enhanced cytokine production; T cell proliferation, survival, and effector function; and immunological memory formation. Targeting of PD-L1 and CD137 with MCLA-145 may achieve synergistic activity by simultaneously blocking the inhibitory checkpoint PD-L1 and activating tumor specific T cells through co-stimulation. Methods We performed combinatorial functional screening of bispecific antibodies generated from high affinity inhibitory Fabs binding PD-L1 combined with a large and diverse panel of agonistic CD137 Fabs. Results MCLA-145 was selected based on its in vitro potency in multiple primary human immune cell assays. Further, it displays an ability to reverse T cell suppression mediated by M2 macrophages or Tregs. MCLA-145 binds to a unique epitope in the cysteine rich domain 2 of CD137 that overlaps with the CD137L binding region, and all potent bAbs in the screen were able to bind to this region. MCLA-145 drives activation of CD137 and the degree of CD137 agonistic activity in T cells correlated with the expression level of PD-L1 on neighboring cells. Using proximity ligation assays and confocal microscopy we demonstrated that MCLA-145 clusters CD137 on the surface of T cells resulting in internalization. The binding location of MCLA-145 on CD137 may be optimal for the formation of ‘immunological synapses’ with PD-L1 expressing antigen presenting cells or tumors resulting in the potent activation of tumor specific cytotoxic T cells. Conclusions These experiments demonstrate the dual anti-cancer activity of MCLA-145 in preclinical models: release of T-cell checkpoint inhibition through PD-L1; and activation and expansion of T cells through CD137, therefore overcoming T-cell exhaustion and increasing T-cell presence/activity (infiltration) in tumors. MCLA-145 is currently undergoing clinical development in an ongoing trial (NCT03922204). Ethics Approval Animal experiments were performed according to guidelines for animal care of the local Animal Experiments Committee; Use of human blood cells from healthy volunteers was approved by the blood bank’s Ethical Advisory Council. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
