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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

Investigating the role of Interleukin 3 and TIM3 for the detection and elimination of Acute Mieloid Leukemia

Research area: Structural Biology

Group leaders: Luca Varani

Researchers:

Status: In progress

Many cancer cells show overexpression of particular proteins that can therefore be targeted by drugs or other therapeutic strategies, at least in theory. In acute myeloid leukemia (AML), a cancer with an high recurrence of relapses due to the presence of Leukemic Stem Cells that are not affected by normal chemotherapic drugs, these leukemic cells differ from normal ones for the strong overexpression of CD123 (IL3 Receptor Alpha) and other proteins such as TIM-3 and CD34 on the cell surface.

We are testing two approaches for selectively targeting AML stem cells with a bio-recognition element capable of discriminating them from normal, healthy cells. Such bio-recognition element could then be linked to either an engineered T-Cell chimeric antigen capable of killing leukemic cells (collaboration with Monza Hospital (IT)) or to nano-vectors capable of delivering drugs or irradiation/heating therapy directly to AML cells (collaboration with EU-Joint Research Center, Ispra (IT)). Previous literature has shown that the approach can succeed in leukemic forms different from AML.

The biggest problem in using overexpressed surface proteins as AML targets is that the bio-recognition element will also target some normal cells that express these proteins at low level. A therapy capable of killing AML cells would, therefore, also kill some normal healthy cells, with deleterious effects. We are attempting to overcome the problem with two complementary strategies. 1) We plan to generate a bi-specific antibody with one antigen binding site capable of recognizing CD123 and a second antigen binding site capable of recognizing TIM3. Both TIM3 and CD123 are expressed on the surface of normal cells but they are not both overexpressed on the same cell as it happens in AML. An antibody that would bind effectively only when it engages both TIM3 and CD123 may be, as a consequence, able to discriminate leukemic from healthy cells. 2) We plan to use either IL3 or an anti-CD123 antibody as bio-recognition element for CD123 (natural receptor alpha for IL3), which is overexpressed in AML cells. In order to avoid unwanted cross-reactivity with healthy cells, we want to investigate the effect of binding affinity on selectivity. Bio-recognition elements with lower binding affinity may engage cells in sufficient number only if their target (e.g. CD123) is abundantly overexpressed, as it is the case in AML cells. In order to tune the binding affinity we are using a combination of experimental methods (solution NMR mapping, mutagenesis, Surface Plasmon Resonance) and computational simulations (docking) to characterize the binding of IL3 and an anti-CD123 antibody to CD123. Visual analysis of the three dimensional structure of CD123 in complex with the aforementioned partners will allow us to design protein mutations with binding affinity lower than the original molecule but still sufficient for successful engagement of leukemic cells.