MCLA-117, a CLEC12AxCD3 bispecific antibody targeting a leukaemic stem cell antigen, induces T cell-mediated AML blast lysis

Pieter Fokko van Loo*, Basav N. Hangalapura, Soley Thordardottir, John D. Gibbins, Henrike Veninga, Linda J.A. Hendriks, Arjen Kramer, Rob C. Roovers, Marij Leenders, John de Kruif, Robert P. Doornbos, Andres Sirulnik, Mark Throsby, Ton Logtenberg, Harry Dolstra, Alexander B.H. Bakker

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Objective: We report the characterization of MCLA-117, a novel T cell-redirecting antibody for acute myeloid leukaemia (AML) treatment targeting CD3 on T cells and CLEC12A on leukaemic cells. In AML, CLEC12A is expressed on blasts and leukaemic stem cells. Methods: The functional capacity of MCLA-117 to redirect resting T cells to eradicate CLEC12APOS tumor cells was studied using human samples, including primary AML samples. Results: Within the normal hematopoietic compartment, MCLA-117 binds to cells expressing CD3 and CLEC12A but not to early myeloid progenitors or hematopoietic stem cells. MCLA-117 induces T cell activation (EC50 = 44 ng/mL), T cell proliferation, mild pro-inflammatory cytokine release, and redirects T cells to lyse CLEC12APOS target cells (EC50 = 68 ng/mL). MCLA-117-induced targeting of normal CD34POS cells co-cultured with T cells spares erythrocyte and megakaryocyte differentiation as well as preserves mono-myelocytic lineage development. In primary AML patient samples with autologous T cells, MCLA-117 robustly induced AML blast killing (23–98%) at low effector-to-target ratios (1:3–1:97). Conclusion: These findings demonstrate that MCLA-117 efficiently redirects T cells to kill tumour cells while sparing the potential of the bone marrow to develop the full hematological compartment and support further clinical evaluation as a potentially potent treatment option for AML.

Original languageEnglish
Pages (from-to)721-733
Number of pages13
JournalExpert Opinion on Biological Therapy
Volume19
Issue number7
DOIs
Publication statusPublished - 3 Jul 2019

Keywords

  • AML
  • bispecific antibody
  • CLEC12A
  • T cell engager
  • T cells

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