Abstract
Pfizer is paying $2.26 billion to acquire Trillium Therapeutics, maker of two clinical-stage fusion proteins directed against CD47, the “do not eat me” signal that cancer cells co-opt to shield themselves from macrophage-mediated killing.
Pfizer is making a $2.26 billion bet on the idea of therapeutically blocking the activity of CD47, the “do not eat me” signal that cancer cells co-opt to shield themselves from macrophage-mediated killing.
In late August, the company announced plans to acquire Trillium Therapeutics, maker of the anti-CD47 fusion proteins TTI-621 and TTI-622, both of which have shown activity in early clinical testing.
“The deal showcases that large pharmaceutical companies have a keen interest in this promising immune checkpoint,” says Kipp Weiskopf, MD, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, MA.
Both TTI-621 and TTI-622 are composed of the same CD47-binding domain from SIRPα, an inhibitory receptor found on macrophages, linked to an immune-activation domain derived from a different subclass of antibody; TTI-621 is more potent at provoking cell death than TTI-622. By inhibiting CD47 on tumor cells and simultaneously rousing an anticancer immune response, the dual function molecules are designed to kick macrophage-mediated cell killing into overdrive—albeit to different degrees, resulting in different therapeutic indices.
Pfizer's move builds on its $25 million investment in Trillium last year. It also comes 16 months after Gilead Sciences paid $4.9 billion to acquire Forty Seven, the company behind magrolimab, a CD47-targeted antibody therapy now in phase III trials for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes.
Blocking the activity of CD47 prevents cancer cells from shielding themselves from macrophage-mediated killing.
Other clinical-stage, macrophage-stimulating agents directed at the same pathway include evorpacept (ALX Oncology), DSP107 (KAHR Medical), lemzoparlimab (AbbVie/I-Mab), CC-90002 (Bristol Myers Squibb), AO-176 (Arch Oncology), and RRx-001 (EpicentRx), among others.
“Just like with PD-1/PD-L1 inhibitors, the pharmaceutical industry now recognizes that CD47/SIRPα-blocking therapies may be effective for many different types of cancer—and may act as a backbone for other therapies,” says Weiskopf, a cofounder of and scientific advisor to ALX.
In phase I testing, TTI-621 and TTI-622, each administered as single-agent therapies to patients with various T- and B-cell lymphomas, yielded responses in up to one third of study subjects. But TTI-621, which carries a strong macrophage-induction signal owing to its IgG1 Fc tail, could be dosed at lower concentrations to achieve the same clinical benefit. TTI-622, which delivers a more moderate “eat me” signal to macrophages due to its IgG4 Fc domain, proved to be more tolerable, less frequently triggering severe drops in platelet count.
According to research analyst Boris Peaker, PhD, of Cowen, an investment bank and financial services company in New York, NY, TTI-622 is “a standout among CD47 assets in development.” The drug's monotherapy activity combined with its safety profile, he points out, suggests it could be “best in class” among CD47-targeted therapeutics.
Trials involving TTI-622 in combination with other drugs for patients with multiple myeloma and AML are ongoing, with studies planned to test the anti-CD47 agent in ovarian and other solid cancers. Meanwhile, evaluations of TTI-621 as a single-agent treatment for peripheral T-cell lymphoma continue, as does a trial testing it with chemotherapy in patients with leiomyosarcoma. Additionally, researchers plan to test both drugs with a PD-1 inhibitor in patients with diffuse large B-cell lymphoma. –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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