TIM-3 Is a Promising Target to Selectively Kill Acute Myeloid Leukemia Stem Cells

Abstract

Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Here we identified T cell immunoglobulin mucin-3 (TIM-3) as a surface molecule expressed on LSCs in most types of AML except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). TIM-3(+) but not TIM-3⁻ AML cells reconstituted human AML in immunodeficient mice, suggesting that the TIM-3(+) population contains most, if not all, of functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden and eliminated LSCs capable of reconstituting human AML in secondary recipients. These data suggest that TIM-3 is one of the promising targets to eradicate AML LSCs.

Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker

“…TIM3 is a candidate for AML LSC-targeted therapeutic monoclonal antibodies, as recently reported (36). The absence of TIM3 expression on functional NBM HSC and residual HSC in AML samples, in contrast to high expression on multiple samples of AML LSC, provides the rationale for developing such antibodies.…”

Leukemic stem cells: identification and clinical application

“…CD33 is, next to leukemic cells, also present on most HSC, on mature and immature myeloid cell and on various progenitors [52], possibly underlying toxicities as found in earlier studies [53]. Anti-CD123 therapy may have similar disadvantages [6], while results of clinical trials targeting newer discovered surface markers more specific for LSC (including CCL-1 [54,55], TIM3 [55][56][57], CD96 [58]), will provide important insights in validity of therapies targeting immunophenotypic markers. Next to specificity, the design of the antibody in terms of conjugates is of importance for effectiveness.…”

Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape

“…Tim-3 blockade would be predicted to additionally interfere with these T-cell extrinsic mechanisms of immunosuppression. In the past few years, two studies have identified Tim-3 as a surface molecule specifically expressed on leukemic stem cells (LSC) but not on normal hematopoietic stem cells (HSC) in AML (28,29). Importantly, anti-Tim-3 antibody was successful in blocking the engraftment of AML after xenotransplantation and eliminating the reconstitution of human AML by LSCs in secondary recipients without interfering with the reconstitution of normal human HSCs.…”

“…Importantly, anti-Tim-3 antibody was successful in blocking the engraftment of AML after xenotransplantation and eliminating the reconstitution of human AML by LSCs in secondary recipients without interfering with the reconstitution of normal human HSCs. These observations raise the intriguing possibility of using a depleting anti-Tim-3 antibody or an anti-Tim-3 antibodydrug conjugate to selectively eliminate LSCs in patients with AML (29). However, whether this is a viable approach in AML awaits experimental data.…”