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Evorpacept

A Cornerstone of Future Oncology Therapy

ALX Oncology's lead therapeutic candidate, evorpacept, is a novel, highly differentiated CD47-targeted investigational therapy.

Learn more by viewing our Publications.

By blocking the “don’t eat me” signal transmitted by CD47 on the surface of cancer cells, evorpacept uniquely reveals these cells to the innate immune system, helping to unleash the full power of the body’s natural defenses against cancer and potentially boosting responses to other important cancer therapies.

In clinical studies across a wide spectrum of tumor types in more than 700 patients to date, evorpacept has demonstrated the potential to serve as a cornerstone therapy upon which the future of immuno-oncology can be built.

Stylized representation of a tumor cell, with evorpacept attached to three CD47 proteins. When evorpacept is attached to CD47, it blocks the “don’t eat me” signal and alerts the immune system to find the tumor.
Visual representation of CD47 attaches to both cancer and healthy red blood cells. We see how CD47 signals “don’t eat me” to the SIRPα receptor on macrophages. The green FC receptor (present on the macrophage) is an important mechanism that when activated can enable an “eat me” signal.

What Is CD47?

CD47 is a protein found on almost all human cells, including red blood cells. It binds to the SIRPα receptor on certain immune system cells (macrophages and dendritic cells), sending a "don't eat me" signal that inhibits absorption by these cells. This action helps protect healthy cells by signaling immune cells, “I belong here – don’t eat me!” However, many tumor cells overexpress CD47, allowing them to evade immune detection and avoid destruction by macrophages.

Previous CD47-Blocking Approaches Fell Short

Other CD47-blocking approaches combine a CD47-binding domain with an active Fc domain, part of an antibody structure that binds to Fc receptors on immune cells to help generate an immune response. These molecules bind to CD47 on the surface of cancer cells and, on their active Fc end, to Fcγ receptors on macrophages and other immune system cells. Ultimately, this action can generate an indiscriminate “eat me” signal against normal cells that is associated with significant side effects and dose-limiting toxicities. In addition, the low CD47 binding affinity of these molecules, combined with dosing limitations, can result in some CD47 receptors on cancer cells remaining unbound and free to exercise their “don’t eat me” signal. This can limit their efficacy in the combination setting.

Representation of how previous CD47 approaches attacked cancer cells, but also how they attacked healthy red blood cells.

Higher affinity CD47 binding

More potently blocks CD47 signal on cancer cells

Robust Clinical Activity

Inactive Fc domain

Less ”sink effect” = more targeted
No known dose-dependent cytopenia = higher dosing

Best-in-Class Safety Profile

Lower molecular weight

Increased solid tumor penetration and higher effective dosing

Strong Solid Tumor Activity

Antibody-like pharmacokinetics

Long half-life = less frequent dosing and matching regimen with combinations

Broad Combination Potential

Designed To Be Different

Evorpacept is a potential best- and first-in-class CD47 checkpoint inhibitor and one of the most advanced checkpoint inhibitors to target and activate the innate immune system.

Our scientists intentionally designed evorpacept to maximize the clinical potential of blocking CD47, while reducing the toxicities associated with previous approaches to CD47 blockade.

Macrophage next to cancer cells with several CD47s. The CD47s send out signals saying, “Don’t eat me.”
Unmask: Evorpacept is now bound to all of the CD47 proteins and the immune system recognizes the tumors.
Unleash: The partner drugs are administered and the immune system can fully attack the tumors.

Greater Benefit, Broader Impact

Research has demonstrated that evorpacept has the potential to enhance the therapeutic activity of many of the most important cancer therapies available today.

This boosting mechanism could expand the impact of immunotherapy and improve outcomes for many patients.

By blocking the "don't eat me" signal transmitted by CD47 on the surface of cancer cells, evorpacept is designed to uniquely reveal these cells to the innate immune system, allowing the body's natural defenses against cancer to engage, and potentially boost responses to other important cancer therapies.

Evorpacept may contribute an additional, differentiated immuno-oncology mechanism to anti-cancer antibodies, checkpoint inhibitors, and antibody-drug conjugates, creating the possibility of a more robust immune response to the disease. These therapies stimulate the immune system to attack cancer, and evorpacept may play a critical role by making cancer cells more visible to this attack.

Evorpacept + Combinations

Click the buttons to learn more about evorpacept in combinations
Evorpacept enables Fc-mediated antibody-dependent phagocytosis by macrophages in combination with anti-cancer antibodies with an active Fc domain, which is otherwise impaired by CD47 expression on cancer cells binding to SIRP alpha on macrophages.
ADCs have also an active Fc (similar to anti-cancer antibodies). They will contribute to the phagocytosis in the same way. In addition, ADCs have a payload and many of the payloads being used now have what is called immunological cell death. The payload kills cells and activates the immune system to recognize antigens in the cancer cells to kill the cancer cells. However, cancer cells that you would expect respond to but aren’t, are also upregulating CD47. By actively blocking CD47, we could allow the immune system to respond to this immunological cell death that the payload is producing.
The most important cells to activate the adaptive immune system are dendritic cells. These cells express SIRP-alpha, the receptor for CD47, and are in constant need of the interaction between CD47 and SIRP-alpha. Therefore, by blocking the cancer cell and DC interaction with evorpacept, dendritic cells can activate T cells (otherwise known as the adaptive immune system). DCs need to be protected by a PD-1 blockade to be mediated by PD-L1 expressing cancer cells. Therefore, once evorpacept has enabled the CD47 blockade, checkpoint inhibitors (Keytruda) are given to the patient to activate T cells by way of the dendritic cells to kill the cancer cells.

Validated Mechanism

Evorpacept is a highly differentiated agent that, due to its proprietary design and the broad expression of CD47 across various cancers, holds the potential to be a significant advancement in cancer care.

Extensive preclinical research utilizing solid tumor and hematologic models indicated that evorpacept binds and blocks CD47 with high affinity. In animal models, this blockade boosted immune activity and improved tumor cell recognition and clearance.

Evorpacept enhanced anti-tumor monoclonal antibody (mAB) and checkpoint inhibitor activity by activating dendritic cells, stimulating macrophage activity, enhancing T-cell activity through cross-priming, and inhibiting immune-suppressive cells that can dampen anti-tumor responses in pre-clinical models. These data supported the clinical approach for evorpacept, which has now exhibited anti-tumor activity in a randomized Phase 2 ASPEN-06 clinical trial.

Explore Our Robust Data

Based on the demonstrated potential of evorpacept, we are advancing a robust clinical program evaluating this novel CD47-blocking therapy in a wide range of cancer indications.

Explore Our Pipeline