820 MCLA-145 is a bispecific IgG1 antibody that inhibits PD-1/PD-L1 signaling while simultaneously activating CD137 signaling on T cells. (9th November 2020)

• Record Type: Journal Article
• Authors: Tacken, Paul; Wang, Liang-chuan; Klooster, Rinse; Loo, Pieter Fokko Van; Zhou, Jing; Mondal, Arpita; Liu, Yao-Bin; Kramer, Arjen; Condamine, Thomas; Volgina, Alla; Hendriks, Linda; Maaden, Hans van der; Rovers, Eric; Engels, Steef; Fransen, Floris; Blanken-Smit, Renate den; Zande, Vanessa Zondag-van der; Basmeleh, Abdul; Bartelink, Willem; Kulkarni, Ashwini; Marissen, Wilfred; Huang, Cheng-Yen; Hall, Leslie; Harvey, Shane; Kanellopoulou, Chrysi; Stewart, Shaun; Nastri, Horacio; Bakker, Lex; Logtenberg, Ton; Plyte, Simon; Mayes, Patrick; Throsby, Mark; Geuijen, Cecile;
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A491
• Page End: A491
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0820
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.