In collaboration with Prof. Irmela Jeremias and Prof. Marion Subklewe, the group of Prof. Karl-Peter Hopfner shows that multi-specific SIRPα-αCD123 fusion antibodies combine a local, tumor cell-restricted CD47 blockade with specific targeting of leukemic stem cells (LSCs) in a single molecule. This concept efficiently eliminates stem cells from acute myeloid leukemia (AML) and minimizes the risk of targeting CD47-positive healthy cells.
The CD47 “don’t eat me” signal is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 shows promising results in clinical trials, but the ubiquitous expression of CD47 on healthy cells poses a risk for antigen sink effects and a potential sites of toxicities, which limits the use of CD47 therapies. In contrast, CD123 is a well-known LSC-specific surface marker and has been used as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of the CD47-SIRPα signaling to AML cells, while specifically enhancing LSC clearance. The results validate SIRPα-αCD123 fusion antibodies as promising therapeutic interventions for AML.
For more information on multi-functional antibodies and CD47 blockade please visit the OPSYON spin-off webpage.
SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells.
Tahk S, Vick B, Hiller B, Schmitt S, Marcinek A, Perini ED, Leutbecher A, Augsberger C, Reischer A, Tast B, Humpe A, Jeremias I, Subklewe M, Fenn NC, Hopfner KP.
J Hematol Oncol. 2021 Sep 27;14(1):155. doi: 10.1186/s13045-021-01163-6.