Preclinical Development of SGN-CD47M: Protease-Activated Antibody Technology Enables Selective Tumor Targeting of the Innate Immune Checkpoint Receptor CD47

CD47 is a cell-surface glycoprotein that is expressed on normal human tissues and plays a key role as a marker of self. Tumor cells have co-opted CD47 overexpression to evade immune surveillance, and thus blockade of CD47 is a highly active area of clinical exploration in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust expression in normal tissues and the toxicities that arise from blocking this inhibitory signal. Furthermore, pro-phagocytic signals are not uniformly expressed in tumors, and antibody blockade alone is often not sufficient to drive antitumor activity. The inclusion of an IgG1 antibody backbone into therapeutic design has been shown to not only serve as an additional pro-phagocytic signal but also exacerbate toxicities in normal tissues. Therefore, a need persists for more selective therapeutic modalities targeting CD47. To address these challenges, we developed SGN-CD47M, a humanized anti-CD47 IgG1 mAb linked to novel masking peptides through linkers designed to be cleaved by active proteases enriched in the tumor microenvironment (TME). Masking technology has the potential to increase the amount of drug that reaches the TME while concomitantly reducing systemic toxicities. We demonstrate that SGN-CD47M is well tolerated in cynomolgus monkeys and displays a 20-fold improvement in tolerability to hematologic toxicities when compared with the unmasked antibody. SGN-CD47M also displays preferential activation in the TME that leads to robust single-agent antitumor activity. For these reasons, SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target the CD47-signal regulatory protein α interaction.