Background Although approved by FDA, anti-CTLA-4 treatment has severe side effect that limits its clinical usage. Blockade of CD47, the “don't eat me” signal, has limited effects in solid tumors despite its potent anti-tumor effects in hematopoietic malignancies. Targeted delivery of immune blockers into tumor tissues are desireble.
Methods Taking advantage of the high expression of CTLA-4 on Treg cells and abundant Fc receptor+ active phagocytes inside the tumor microenvironment (TME), we design and test an anti-CTLA-4×SIRPα (CD47 ligand)-Fc heterodimer that selectively blocks CD47 on intratumoral Treg cells and increases antibody-dependent cellular phagocytosis (the “eat me” signal).
Results Anti-CTLA-4×SIRPα preferentially depletes ICOShigh immunosuppressive Treg cells in the TME (figure 1–3) and enhances immunity against solid tumors. Mechanistically, we discovered that CD47 expression on Treg cells limits anti-CTLA-4 mediated depletion while Fc on the heterodimer enhances the depletion. Furthermore, anti-human CTLA-4×SIRPα depletes tumor Treg cells (figure 4–6) and exhibits less toxicity than anti-human CTLA-4 in a humanized mouse model.
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