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Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies

Science  05 Jul 2013:
Vol. 341, Issue 6141, pp. 88-91
DOI: 10.1126/science.1238856

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Immunotherapy Packs a One-Two Punch

Despite the immune system's best efforts, cancer always seems to be one step ahead. One example of this is that tumor cells express CD47 on their cell surface. CD47 acts as a “don't eat me” signal to phagocytic macrophages. A potential therapeutic strategy could thus be to block this signal. Weiskopf et al. (p. 88, published online 30 May; see the Perspective by Kershaw and Smyth) created variants of the CD47 receptor, SIRPα, that could act as high-affinity antagonists of CD47. Although the antagonists blocked CD47 effectively in tumor-bearing mice, on their own they did not induce macrophages to phagocytose the tumor cells. When paired with a variety of therapeutic antitumor antibodies, however, the CD47 antagonists were very effective in treating several mouse tumor models.

Abstract

CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This “one-two punch” directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.

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