Blocking the CD47 “do not eat” signal with SIRPaFc

The phagocytic activity of macrophages is regulated by both activating ("eat") and inhibitory ("do not eat") signals. CD47, a widely expressed transmembrane glycoprotein, serves as a critical "do not eat" signal inhibiting phagocytosis by binding to signal regulatory protein alpha (SIRPα) on the surface of macrophages. CD47 is believed to regulate the natural clearance of ageing erythrocytes and platelets by macrophages. In addition, the CD47–SIRPα interaction may represent an important mechanism by which malignant cells escape immune-mediated clearance. CD47 has been shown to be overexpressed in numerous blood cancers, such as acute myeloid leukemia and lymphoma, and solid tumors. CD47 has been found to be an adverse prognostic factor, where high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. These findings suggest that tumor cells exploit the suppressive CD47–SIRPα axis to evade macrophage-mediated destruction. Blocking CD47 has thus emerged as a promising therapeutic strategy and numerous studies have shown that interrupting the CD47–SIRPα signaling pathway promotes anti-tumor activity against human cancers both in vitro and in vivo.

Our approach to blocking CD47 is to use a decoy receptor (SIRPαFc) format. SIRPαFc consists of the CD47-binding domain of human SIRPα linked to an Fc region of 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. Furthermore, Trillium is developing two SIRPαFc decoy receptors (TTI-621 and TTI-622) that carry different Fc regions, which allow us to tune the amount of Fc "eat" signal that macrophages receive.

Expanding our CD47 Pipeline with TTI-622

The ability of SIRPαFc to induce human macrophages to eat human tumor cells is readily demonstrated in laboratory studies (see figure below). This effect is seen across a range of both blood and solid cancers. In animal studies, SIRPαFc treatment results in clear antitumor effects. On the basis of these results, two clinical trials are underway with TTI-621. For more information on Trillium’s clinical studies, please see our Clinical Trials page.

tumor-cells

Tumor cells from an AML patient (labeled with a green dye) were incubated with human macrophages (labeled with a red dye) in the presence of TTI-621 or a control protein. After 2 hours, confocal microscopy was performed. Phagocytosis of the green tumor cells is clearly visible after TTI-621 treatment. Some macrophages can be seen to have ingested more than 5 tumor cells.

In addition to their direct anti-tumor activity, macrophages can also function as antigen-presenting cells and stimulate antigen-specific T cells. Thus it is possible that increasing tumor cell phagocytosis after SIRPαFc exposure may result in enhanced adaptive immunity. In support of this, CD47 antibody blockade has been shown to prime an anti-tumor cytotoxic T cell response in mice and we presented data demonstrating that TTI-621 can augment antigen-specific T cell responses in vitro.

Thus 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 (see figure below).

tumor-steps

CD47 on the tumor cell provides a suppressive, anti-phagocytic signal to macrophages through SIRPα (Step A). SIRPαFc binds CD47 on the tumor cells (Step B) and engages FcγRs on the macrophages (Step C) resulting in tumor cell phagocytosis (Step D). Following phagocytosis, tumor cell antigens are processed and presented by macrophages as MHC-peptide complexes to T cells (Step E), resulting in T cell activation and tumor cell destruction (Step F).

Trillium’s SIRPαFcs are not the only agents being developed to block CD47. There are a number of other drug types in development, including CD47-specific antibodies, a CD47 bispecific antibody, a mutated high affinity SIRPαFc and a SIRPα-specific antibody. Several of these agents are being tested in early-stage clinical trials. We believe that our approach has advantages over our competitors. Notably, our SIRPαFcs do not bind appreciably to human red blood cells compared to anti-CD47 antibodies. 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 minimize interference with laboratory blood typing tests. In addition, the IgG1 Fc region of TTI-621 may also assist in the activation of macrophages by engaging Fc receptors, and thus confer greater potency than IgG4-based antibodies.

SIRPαFc
Quick Facts

SIRPαFc targets CD47, a molecule highly expressed in many types of cancer cells

CD47 delivers a "do not eat" signal to macrophages

SIRPαFc is a fusion protein that prevents cancer cells from delivering a "do not eat" signal

A Phase 1 clinical trial (NCT02663518) is evaluating SIRPαFc (TTI-621) in advanced hematologic malignancies, and a second Phase 1 trial (NCT02890368) is ongoing in solid tumors 

TTI-622 is an IgG4 SIRPαFc protein, which is primarily being developed for combination therapy

Two unique SIRPαFc agents are in development for monotherapy and combination studies

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