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883 MCLA-145, an anti CD137×PD-L1 bispecific antibody, induces T cell activation and proliferation in ex vivo models of hepatocellular carcinoma
  1. Jyaysi Desai1,
  2. Lissane Noordam1,
  3. Patrick Boor1,
  4. Rachid Bouzid2,
  5. Diana Mittag2,
  6. Paul Tacken2,
  7. Jeroen Lammerts van Bueren2,
  8. Cecile Guijen2,
  9. Jaap Kwekkeboom1,
  10. Dave Sprengers1 and
  11. Sonja Buschow1
  1. 1Erasmus Medical Center, Rotterdam, Netherlands
  2. 2Merus N.V., Utrecht, Netherlands


Background Costimulatory molecules, such as CD137 (4-1BB), have emerged as promising targets for cancer immunotherapy. Despite promising results in animal tumor models, clinical trials with CD137 agonists have had limited success due to both dependency on FcgR-mediated clustering and dose limiting hepatotoxicity. Merus has developed an Fc-silenced Biclonics® CD137×PD-L1 antibody, MCLA-145, whose stimulatory activity is correlated with PD-L1-mediated CD137 clustering which is designed to be preferentially confined to the PD-L1 expressing tumor microenvironment. The aim of this study was to characterize the mechanism of action of MCLA-145 in resected hepatocellular carcinoma (HCC), a heterogenous solid tumor with limited therapeutic options. We studied target expression and ex vivo responses in human HCC tumor-infiltrating lymphocytes (TIL).

Methods Lymphocytes and myeloid cells isolated from resected HCC (n=10) tumors (TIL), paired tissues adjacent to tumor (TFL) and peripheral blood were characterized for CD137, PD-1 and PD-L1 expression by flow cytometry. Additionally, TIL proliferation upon either anti-CD3/CD28 stimulation or autologous B cell blasts electroporated with tumor-associated antigens (TAA) glypican-3 (GPC3) and/or melanoma-associated antigen (MAGE)-C2 stimulation was assessed ex vivo in presence of MCLA-145, its bivalent monospecific parental mAbs, the bivalent mAbs urelumab (anti-CD137) or atezolizumab (anti-PD-L1) or isotype control.

Results Compared to lymphocytes derived from adjacent tissues and blood, CD137 and PD-1 expression was found to be highest in TIL, and specifically on activated regulatory T cells. CD137 was also found to be expressed on myeloid cells such as tissue resident Kupffer cells and granulocytes. PD-L1 was mainly found to be expressed on CD3- cells. Treatment with MCLA-145 led to increased proliferation, as measured by Ki67 staining, of HCC-derived CD8+ TILs, compared to isotype control treatment. Expression of CD137 was significantly increased on these proliferating CD8 T cells upon the treatment with MCLA-145. Additionally, MCLA-145 enhanced CD8+ TIL proliferation more potently compared to its bivalent monospecific parent mAbs or Urelumab.

Conclusions Biclonics® antibody MCLA-145 has the capacity to enhance activation and proliferation of tumor-derived CD8+ T cells in the PD-L1 expressing tumor microenvironment of HCC ex vivo, warranting further evaluation in HCC.

Ethics Approval Ethical approval (METC) for this study has been obtained.

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