Trillium is developing biologics to enhance the ability of the patient’s own immune system to detect and destroy cancer cells. Our lead programs, TTI-621 and TTI-622, are directed against CD47, an innate immune checkpoint that functions as a “don’t eat me” signal to the immune system.
CD47 delivers a “don’t eat me” signal to macrophages through its interaction with SIRPα, allowing cancer cells to escape the immune system.
The phagocytic activity of macrophages is regulated by both activating (“eat me”) and inhibitory (“don’t eat me”) signals. CD47 serves as a critical “don’t eat me” signal inhibiting phagocytosis by binding to signal regulatory protein alpha (SIRPα) on the surface of macrophages. The CD47-SIRPα interaction represents an important mechanism by which malignant cells evade macrophage-mediated destruction. CD47 is overexpressed in numerous hematological cancers and solid tumors, and high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. Preclinical studies have shown that interrupting the CD47-SIRPα signaling pathway promotes anti-tumor activity against human cancers, both in vitro and in vivo. Thus, blocking CD47 has emerged as a promising therapeutic strategy with early clinical data demonstrating benefit to cancer patients.
Developing two unique SIRPαFc decoy receptors to prevent cancer cells from escaping the immune system and triggering their destruction.
Our approach to blocking CD47 is to use a decoy receptor (SIRPαFc). SIRPαFc consists of the CD47-binding domain of human SIRPα linked to an Fc region of a human immunoglobulin (antibody). It is a dual function molecule, designed to 1) bind CD47 and neutralize its suppressive signal, and 2) deliver a pro-phagocytic (“eat me”) signal through the Fc region, which binds to activating Fc receptors on the surface of macrophages. We believe the combination of these two events – blockade of the negative CD47 “don’t eat me” signal and delivery of a positive Fc “eat me” signal – is a particularly effective way to enable macrophages to destroy tumor cells. Trillium is developing two SIRPαFc decoy receptors (TTI-621 and TTI-622) that differ in the Fc region allowing us to tune the amount of Fc “eat me” signal that macrophages receive.
Blocking CD47 with SIRPαFc decoy receptors may activate both the innate and the adaptive immune systems.
The innate immune system forms the body’s first line of defense against invaders but its potential to fight tumors has long been ignored. Our SIRPαFc decoy receptors are designed to activate cells of the innate immune system to phagocytose and destroy tumor cells. This effect is seen across a range of both blood and solid cancers. In addition to their direct anti-tumor activity, cells of the innate immune system play a key role in recruiting and activating the adaptive immune system, which provides specificity and memory. We envision a mechanism by which SIRPαFc blocks the CD47 “don’t eat me” signal and engages activating Fc receptors on macrophages, leading to tumor cell phagocytosis, increased antigen presentation and enhanced T cell responses, thus bridging both innate and adaptive immunity (see figure).
Our decoy receptors set us apart from others in the field.
We believe that our approach has advantages over our competitors. TTI-621 is a SIRPαFc fusion protein that consists of the extracellular CD47-binding domain of human SIRPα, linked to the Fc region of human IgG1. It is a potent dual function molecule that is designed to inhibit CD47 on the tumor cell and simultaneously deliver a strong activating signal to the immune system, whereas most competitor CD47 blockers require an additional drug for full activation. TTI-622 is a second SIRPαFc that consists of the same SIRPα domain as TTI-621 but linked to the Fc region of human IgG4. TTI-622 inhibits CD47 to the same degree as TTI-621 but delivers a less potent activation signal to the immune system, allowing for higher dosing and tuning of the activation signal. Importantly, both of Trillium’s SIRPαFc decoy receptors are differentiated from many competitor molecules by virtue of not binding to CD47 on human red blood cells. This lowers the risk of serious anemia in patients, avoids the removal of the drug from the circulation by red blood cells (“antigen sink effect”) and minimizes interference with laboratory blood typing tests.
