CD47-SIRPα Drug Target Minireview
In Aug. 2021, immuno-oncology company, Trillium Therapeutics, was acquired by Pfizer for $2.3 billion, adding Trillium’s two CD47-targeting biologics, TTI-621 and TTI-622, to Pfizer’s oncology pipeline. The acquisition followed Gilead’s $4.9B buyout of Forty Seven in early 2020, after clinical data was presented on Forty Seven’s lead, the anti-CD47 monoclonal antibody, magrolimab. Magrolimab was granted breakthrough therapy designation by the FDA for myelodysplastic syndrome (MDS) and is currently the most advanced anti-CD47 therapy in the clinic. Here is a target minireview to get readers caught up on the science behind this emerging therapeutic axis.
CD47 – A Checkpoint for Innate Immune Cell Activity
Cancer immunotherapy has been a hot area in clinical development for some time thanks to the success of anti-PD-1/L1 and anti-CTLA-4 checkpoint inhibitors. Checkpoints like PD-1 can be thought of as “don’t kill me” signals on cancer cells, preventing T-cells from clearing tumors (there are additional mechanisms, but the framework is useful). Blocking checkpoints like PD-1 allows T-cells to proceed with killing tumors, leading in some cases to durable tumor regression.
If T-cells can be activated by checkpoint inhibitors against cancers, are there similar checkpoints whose inhibition could allow innate immune cells like neutrophils or macrophages to be turned against tumors? In the late 1980s to early 1990s, scientists led by Eric Brown developed an antibody that inhibited peptide-enhanced phagocytosis (by neutrophils) and identified its antigen to be a 50 kDa transmembrane protein belonging to the immunoglobulin superfamily. This antigen with a role in phagocytosis turned out to be CD47.
Figure 1. The interaction between CD47 and Signal Regulatory Protein α (SIRPα) elicits the intracellular phosphorylation of SIRPα and subsequent downstream signalling events that tell phagocytic cells like macrophages not to engulf the cell it’s confronting (“don’t eat me”). Inhibiting this CD47/SIRPα signalling process can lead to the phagocytosis of tumor cells. Image generated with PDB structures: 2WNG, 4CMM, and 7MYZ.
Scientists led by Stanford’s Irving Weissman later discovered that directly blocking CD47 in tumor cells led to macrophage-mediated phagocytosis of such cells (e.g. acute myeloid leukemia stem cells, metastatic leiomyosarcoma cells, and liver cancer cells). The potential importance of CD47 as a “don’t eat me” checkpoint signal was not lost on Weissman’s team amidst the immunotherapy boom. In 2014, Weissman co-founded Forty Seven as a Stanford spinout to develop CD47 inhibitors, and the anti-CD47 mAb from Forty Seven, Hu5F9-G4 (magrolimab), soon became the first CD47 inhibitor to be tested in clinical trials.
Overcoming On-Target Anemia – a Challenge for CD47 Drug Discovery
Because CD47 is expressed on both tumor cells and healthy blood cells, CD47-targeting agents have the potential to cause premature turnover of healthy cells, resulting in anemia and thrombocytopenia (reviewed here). This effect has been observed in a number of preclinical animal models and in humans. Several strategies have been employed to maximize the therapeutic index of CD47-targeting drugs or manage their effects clinically. Four clinical candidates are highlighted below to illustrate strategies to overcome this challenge – a more comprehensive list of molecules targeting this axis can be found here.
