Unlocking the Potential of TTI-622: Enhancing Antitumor Immunity and Overcoming Resistance in Hematologic and Solid Tumors

Tumor cells often escape immune detection by macrophages through elevated CD47 levels, which interact with the SIRPα receptor and send an anti-phagocytic signal. A new soluble SIRPα-Fc variant, TTI-622, which features an IgG4 Fc tail, was evaluated for its ability to block the CD47-SIRPα interaction and enhance macrophage-mediated tumor cell phagocytosis, both in vitro and in vivo.

TTI-622 shows minimal binding to human red blood cells and no hemagglutination, reducing the risk of anemia compared to CD47-blocking antibodies. It effectively promotes the phagocytosis of a wide range of tumor cells from patients with both liquid and solid cancers, with a preference for tumor cells over platelets in competitive assays.

In vivo studies demonstrated TTI-622's significant tumor growth inhibition and survival benefits as a monotherapy in a DLBCL xenograft model. When combined with daratumumab in Burkitt lymphoma and multiple myeloma models, TTI-622 enhanced the therapeutic effects. Notably, the combination of TTI-622 with cetuximab in a non-responsive head and neck cancer model led to a significant decrease in tumor growth and improved survival.

These findings indicate that TTI-622 can effectively stimulate macrophage phagocytosis in various types of cancer and, when combined with other antibodies, can increase the efficacy of treatments for both hematological and solid tumors. This supports the potential of TTI-622 as a clinical candidate for use in combination therapies for cancer patients.

The research was presented by Gloria H. Y. Lin and colleagues at the American Association for Cancer Research Annual Meeting in 2018.