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820 MCLA-145 is a bispecific IgG1 antibody that inhibits PD-1/PD-L1 signaling while simultaneously activating CD137 signaling on T cells
  1. Paul Tacken1,
  2. Liang-chuan Wang2,
  3. Rinse Klooster1,
  4. Pieter Fokko Van Loo1,
  5. Jing Zhou2,
  6. Arpita Mondal2,
  7. Yao-Bin Liu1,
  8. Arjen Kramer1,
  9. Thomas Condamine2,
  10. Alla Volgina2,
  11. Linda Hendriks1,
  12. Hans van der Maaden1,
  13. Eric Rovers1,
  14. Steef Engels1,
  15. Floris Fransen1,
  16. Renate den Blanken-Smit1,
  17. Vanessa Zondag-van der Zande1,
  18. Abdul Basmeleh1,
  19. Willem Bartelink1,
  20. Ashwini Kulkarni2,
  21. Wilfred Marissen1,
  22. Cheng-Yen Huang2,
  23. Leslie Hall2,
  24. Shane Harvey2,
  25. Chrysi Kanellopoulou2,
  26. Shaun Stewart2,
  27. Horacio Nastri2,
  28. Lex Bakker1,
  29. Ton Logtenberg1,
  30. Simon Plyte1,
  31. Patrick Mayes2,
  32. Mark Throsby1 and
  33. Cecile Geuijen1
  1. 1Merus NV, Utrecht, Netherlands
  2. 2Incyte Corporation, Wilmington, DE, USA


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.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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