Science

Evorpacept Mechanism of Action

We are a clinical-stage immuno-oncology company focused on helping patients fight cancer by developing therapies that block the CD47 checkpoint pathway and bridge the innate and adaptive immune system. Cancer cells leverage CD47, a cell surface protein, as a “don’t eat me” signal to evade detection by the immune system.

Our company is developing a next-generation checkpoint inhibitor designed to have a high affinity for CD47 and to avoid the limitations caused by hematologic toxicities inherent in other CD47 blocking approaches.

We believe our lead product candidate, evorpacept (ALX148), will have a wide therapeutic window to block the “don’t eat me” signal on cancer cells, and to leverage the immune activation of broadly used anti-cancer agents through combination strategies.

CD47 is a Myeloid Checkpoint Target

Cancer cells evade phagocytosis by up-regulating CD47, a transmembrane protein that mainly functions as an anti-phagocytic “don’t eat me” signal for healthy cells. CD47 interacts with its cognate receptor SIRPα, a regulatory membrane glycoprotein, that is expressed on macrophages and other myeloid cells and serves to prevent phagocytosis when bound to CD47. By overexpressing CD47, cancer cells are able to avoid phagocytosis by macrophages and thereby evade subsequent detection by the adaptive immune system. High CD47 expression in cancer cells has been shown to be a prognostic indicator of decreased survival in multiple oncology indications.

Data generated by us and others in the field have demonstrated that activating the immune system against cancer requires both blocking phagocytosis checkpoints and inducing pro-phagocytic signals. This can be achieved by combining CD47 blockade with either conventional chemotherapies or targeted therapies, which together promote phagocytosis by macrophages and maximize adaptive immune system response.

Existing anti-cancer therapeutics can increase “eat me” signals on cancer cells. For example, azacitidine activates the immune system by increasing the display of calreticulin on cancer cells. Calreticulin is an important example of a pro-phagocytic “eat me” signal that potentiates immune response when expressed on cancer cells. Therapeutic antibodies that target tumor-specific antigens, such as the HER2 receptor, also induce cellular phagocytosis, but through a slightly different mechanism. These antibodies direct macrophages to cancer cells by binding to the tumor-specific antigen and activating the macrophage by engaging the Fcγ receptors to induce phagocytosis. However, if CD47 is not blocked, the “don’t eat me” signal can limit the activity of this mechanism. CD47 blocking therapies can therefore maximize a combination agent’s clinical efficacy by overcoming the “don’t eat me“ signal that is co-opted by cancer cells.

Our lead product candidate, evorpacept, targets CD47 to maximize phagocytosis of cancer cells and activate the adaptive immune system.

Evorpacept: Advantages of ALX’s Approach to Blocking CD47

We founded ALX Oncology because we believed the limitations described above would prevent CD47 blockade from reaching its full potential as a therapy for patients with cancer. From the company’s inception, we designed evorpacept to overcome these limitations and to maximize the utility of CD47 blockade as an effective anti-cancer therapeutic for a broad range of tumors. We believe evorpacept’s broader therapeutic window will allow for greater drug exposure than other CD47 blocking agents potentially translating into improved efficacy in both hematological and solid tumors. To date, we have not yet reached a maximum tolerated dose for evorpacept.

Our lead product candidate, evorpacept, is a next generation CD47 blocking therapeutic that combines a high-affinity CD47 binding domain with an inactivated, proprietary Fc domain.

The CD47 binding domain of evorpacept is an affinity enhanced extracellular domain of signal regulatory protein alpha, or SIRPα, a protein that is the natural receptor to CD47 found on myeloid cells. We have engineered the Fc domain of evorpacept so that it does not provide a pro-phagocytic signal while still maintaining an antibody-like pharmacokinetic half-life for the molecule. We believe our inactive Fc approach improves tolerability when compared to other CD47 blocking approaches that have an Fc domain that engages activating receptors on macrophages, causing phagocytosis and death of healthy cells in addition to cancer cells. Furthermore, evorpacept is approximately one-half the molecular weight of a typical antibody. Evorpacept’s lower molecular weight enables it to deliver the molar equivalent of an antibody at one half the dose. For example, a 30 mg/kg dose of evorpacept, the highest level that we have dosed to date, is approximately equivalent to a 60 mg/kg dose of an antibody. Evorpacept’s lower molecular weight may also facilitate increased solid tumor penetration and provide greater potency within the tumor microenvironment.

Evorpacept: Meticulously Designed CD47 Blocker

Publications

  • ASPEN-01: A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Trastuzumab, Ramucirumab, and Paclitaxel in Patients with 2nd Line HER2-Positive Advanced Gastric or Gastroesophageal Cancer View poster (ESMO-GI 2021)
  • ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma; ASPEN-01 View slides (ASH 2020)
  • ALX148 Enhances the Depth and Durability of Response to Multiple AML Therapies View slides (ASH 2020)
  • Targeting the Myeloid Checkpoint Receptor SIRPα Potentiates Innate and Adaptive Immune Responses to Promote Anti‑Tumor Activity View article (JHO 2020)
  • ALX148, a CD47 Blocker, in Combination with Standard Chemotherapy and Antibody Regimens in Patients with Gastric/Gastroesophageal Junction (GC) Cancer and Head and Neck Squamous Cell Carcinoma (HNSCC); ASPEN-01 View poster (SITC 2020)
  • Assessing and Mitigating the Interference of ALX148, a Novel CD47 Blocking Agent, in Pretransfusion Compatibility Testing View article (Transfusion 2020)
  • ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma View poster (EHA 2020)
  • A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Standard Anti Cancer Antibodies and Chemotherapy Regimens in Patients with Advanced Malignancy View poster (ASCO 2020)
  • A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma View poster (ASH 2019)
  • Pharmacodynamic Biomarker Characterization of ALX148, a CD47 Blocker, in Combination with Established Anticancer Antibodies in Patients with Advanced Malignancy View poster (SITC 2019)
  • Discovery of High Affinity, Pan-Allelic, and Pan-Mammalian Reactive Antibodies Against the Myeloid Checkpoint Receptor SIRPα Read article (mAbs 2019)
  • A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Established Anticancer Antibodies in Patients with Advanced Malignancy View poster (ASCO 2019)
  • Antibodies to SIRPα Enhance Innate and Adaptive Immune Responses to Promote Anti-Tumor Activity View poster (AACR 2019)
  • Discovery of Monoclonal Antibodies Targeting Myeloid Checkpoint SIRPα to Enhance Anti-Tumor Immunity View poster (Keystone 2019)
  • ALX148 Blocks CD47 and Enhances Innate and Adaptive Antitumor Immunity with a Favorable Safety Profile Read article (PLOS ONE 2018)
  • A Phase 1 Study of ALX148: CD47 Blockade in Combination with Anti-Cancer Antibodies to Bridge Innate and Adaptive Immune Responses for Advanced Malignancy View poster (SITC 2018)
  • Pharmacokinetic and Pharmacodynamic Characterization of ALX148, a CD47 Blocker, in Patients with Advanced Malignancy and Non-Hodgkin Lymphoma View poster (SITC 2018)
  • Oral Presentation: A Phase 1 Study of ALX148: CD47 Blockade in Combination with Anti-Cancer Antibodies to Bridge Innate and Adaptive Immune Responses for Advanced Malignancy View slides (SITC 2018)
  • A Phase 1 Study of ALX148, a CD47 Blocker, Alone and in Combination with Established Anti-Cancer Antibodies in Patients with Advanced Malignancy and Non Hodgkin Lymphoma View poster (ASCO 2018)
  • Oral Presentation: ALX148 is a High Affinity SIRPα Fusion Protein that Blocks CD47, Enhances the Activity of Anti-Cancer Antibodies and Checkpoint Inhibitors, and Has a Favorable Safety Profile in Preclinical Models View slides (ASH 2017)
  • ALX148 is a High Affinity SIRPα Fusion Protein that Blocks CD47, Enhances the Activity of Anti-Cancer Antibodies and Checkpoint Inhibitors, and Has a Favorable Safety Profile in Preclinical Models View abstract (Blood 2017)
  • A First-in-Human Study of ALX148: CD47 Blockade to Enhance Innate and Adaptive Immunity for Advanced Solid Tumor Malignancy and Non-Hodgkin Lymphoma View poster (SITC 2017)