Background Overexpression of CD47 by tumor cells exploits an immune checkpoint preventing tumor recognition and destruction by innate immune cells. Binding of tumor CD47 to SIRPα on macrophages and dendritic cells triggers a ‘don’t eat me’ signal that inhibits phagocytosis and allows escape from innate immune surveillance. Blockade of the CD47/SIRPα axis, however, enables immune recognition and phagocytic clearance of tumor cells. We have developed a clinical stage CD47 targeting antibody AO-176 that is highly differentiated among agents in this class. AO-176 not only blocks the CD47/SIRPα interaction and induces phagocytosis of tumor cells, but it also has a direct killing mechanism (via PCDIII) and induction of immunogenic cell death, leveraged by preferential binding to tumor versus normal cell CD47.
Methods CD47 and β1 integrin expression and localization were evaluated using a combination of flow cytometry, western blotting, confocal microscopy and immunohistochemistry.
Results Previously, we described that the preferential binding of AO-176 to tumor versus normal cells was due to its interaction with CD47 molecules that were pre-complexed to β1 integrin. This finding was particularly important and suggestive of why AO-176 does not bind red blood cells since they do not express β1 integrin. We have extended these findings to show that β1 integrin as well as CD47 are also expressed at lower levels in normal versus tumor cells, and that solid and hematologic tumor cells overexpress both CD47 and β1 integrin which correlate with poor prognosis in cancer. In addition, we show that AO-176 is able to bind and occupy CD47/β1 integrin complexes to a greater extent at acidic versus physiologic pH such as would be found in tumor microenvironments, an observation that also contributes to the enhanced targeting of AO-176 to tumor cells. Taken together, these findings add further insight into the preferential binding of AO-176 to tumor versus normal cells.
Conclusions The context dependent binding of AO-176 to CD47, when complexed to β1 integrin, is unique among CD47 axis targeting agents and together with its direct killing mechanism of action offers a potentially better safety profile and opportunity for a therapeutic advantage. AO-176 is currently being evaluated in Phase 1 clinical trials for the treatment of patients with select solid tumors (NCT03834948) and multiple myeloma (NCT04445701).
Trial Registration NCT03834948, NCT04445701.
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.