Our story begins back in the early 2000s when a biologist by the name of Irving Weissman discovered that leukemia cells produce high levels of a protein called CD47. This was odd because CD47 was better known for its function in healthy blood cells. CD47 flags a cell as a friendly, thus telling a passing white blood cell to hold its fire. Cancers utilize this to their advantage, using CD47 as a Trojan horse of sorts, thereby masquerading as healthy blood cells so the body will leave them alone.
Initial petri dish models by Weissman and his team showed that the introduction of CD47-blocking antibodies (Y-shaped proteins created with the sole purpose of knocking off CD47 proteins) would alert macrophages (a type of immune cell) to the presence of the cancer. When tests moved to living subjects, the introduction of the CD47 antibodies were found to cure some cases of lymphomas and leukemias when human-versions were transplanted into mice.
This was almost a decade ago. Weissman and his team have since found CD47 not only in blood cancers but on every single human primary tumor they tested. It gets better: after transplanting various human tumors into mice, the injection of CD47 antibodies produced positive results no matter the type of cancer, with reports of tumors shrinking and failing to metastasize.
However, since mice are not tiny, hairy, adorable exact replicas of humans, they need to test on humans. Thankfully Weissman’s lab recently received a $20 million grant from the California Institute for Regenerative Medicine to conduct studies on humans.
But, anti-bodies have their drawbacks. Along with various adverse side effects for the subject receiving them, anti-bodies are relatively large and thus cannot always penetrate tumors. Thus, Weissman's group has recently teamed up with structural biologist Christopher Garcia to find an alternate approach to blocking CD47.
Garcia and Weissman began with a study of SIRPα, a protein that serves as a sort of antenna on the surface of macrophages. SIRPα connects with CD47 to receive the tumor cell’s, "don't eat me" signal, as it is referred to in Weissman’s original study. Their hope was to create a free-floating, synthetic form of SIRPα that could prevent the macrophage’s real SIRPα from attaching to the cancer cell. Thus, with the cancer cell’s “do not eat me” signal jammed, the immune cell would attack the cancer.
Garcia’s lab was able to synthesize two forms of SIRPα that bound 50,000 times more tightly to CD47 than the natural SIRPα receptor. However, when the lab moved to petri dish modeling, they found that the macrophages still ignored the cancer cells, despite the addition of the synthetic SIRPα. However, the lab found that a combination of a tumor-specific antibody drug, which drew the attention of the macrophages to the cancer, and the synthetic SIRPα could get the job done. When the combination was tested on mice, it was found that tumors often shrank faster or all out disappeared.
While the outlook is certainly hopeful, further testing on humans is still required. But because the synthetic SIRPα proteins are “relatively nontoxic,” Garcia and Weissman are hopeful that they will be able to develop an experimental drug and move to human trials soon.