Developing novel immunotherapies for cancer with a focus on CD47 blockade
Trillium utilizes biologic- and small molecule-based approaches to enhance the ability of the patient’s own immune system to detect and destroy cancer cells. Our lead programs are directed against CD47, an immune checkpoint inhibitor that functions as a “do not eat” signal. We are also developing novel fluorine-based small molecules directed against other immuno-oncology targets in our discovery program.
CD47 delivers a “do not eat” signal to macrophages through its interaction with SIRPα, allowing cancer cells to escape the immune system.
Escaping the immune system
The phagocytic activity of macrophages is regulated by both activating (“eat”) and inhibitory (“do not eat”) signals. CD47 serves as a critical “do not eat” signal inhibiting phagocytosis by binding to signal regulatory protein alpha (SIRPα) on the surface of macrophages. The CD47–SIRPα interaction may represent an important mechanism by which malignant cells evade macrophage-mediated destruction. CD47 is overexpressed in numerous blood cancers and solid tumors, and high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. Thus, blocking CD47 has emerged as a promising therapeutic strategy with numerous studies showing that interrupting the CD47–SIRPα signaling pathway promotes anti-tumor activity against human cancers in vitro and in vivo.
Developing two unique SIRPαFc decoy receptors to prevent cancer cells from escaping the immune system and triggering their destruction.
No escape on our watch
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”) 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 “do not eat” signal and delivery of a positive Fc “eat” 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” signal that macrophages receive.
Blocking CD47 with SIRPαFc decoy receptors may activate both the innate and the adaptive immune systems.
Innate to adaptive
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 “do not eat” 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.
A differentiated approach
We believe that our approach has advantages over our competitors. Our lead CD47 blocker, TTI-621, is a potent, dual function molecule that is designed to inhibit CD47 on the tumor cell and simultaneously deliver an activating signal to the immune system, whereas most competitor CD47 blockers require a second drug for full activation. In addition, Trillium’s SIRPαFc decoy receptors do not bind to normal human red blood cells. This may lower the risk of inducing anemia in patients, may avoid the removal of drug from circulation by red blood cells (“antigen sink effect”), and may minimize interference with laboratory blood typing tests.
Combining our expertise in synthetic chemistry and immuno-oncology to create tomorrow’s breakthroughs.
Trillium is employing our proprietary fluorine chemistry platform to expand our immuno-oncology pipeline. Under carefully defined conditions, fluorination can improve potency, stability and safety, and other critical drug attributes. Innovative breakthroughs by Fluorinov Pharma, which was acquired by Trillium in 2016, enable unique, proprietary fluorine chemical synthesis that has the potential to transform promising compounds into superior drugs. Using this platform in combination with our expertise in immuno-oncology, we have undertaken several new discovery projects addressing novel immunologic targets.