Cusatuzumab is a humanized monoclonal antibody, a type of targeted therapy designed to treat certain cancers. This investigational biological drug is engineered to interact with specific molecular structures on diseased cells. The goal of this precision medicine is to selectively eliminate malignant cells while minimizing damage to healthy tissues.
The Target: CD70 Protein
The premise of Cusatuzumab’s function rests on the presence of the Cluster of Differentiation 70 (CD70) protein on the surface of cancer cells. Under normal physiological conditions, CD70 is a member of the Tumor Necrosis Factor (TNF) family. Its expression is tightly regulated, appearing only transiently on highly activated immune cells such as T cells and B cells. Its role is to interact with its receptor, CD27, to provide a costimulatory signal that promotes the proliferation and survival of these immune cells during an immune response.
In cancer, the expression of CD70 becomes aberrantly sustained and widespread, especially across various hematological malignancies. For instance, over 95% of immature white blood cells (blasts) from patients with newly diagnosed Acute Myeloid Leukemia (AML) express CD70. This continuous presence allows the cancer to exploit the CD70/CD27 signaling pathway, which provides pro-survival signals that fuel the disease’s growth and persistence. Targeting this protein disrupts the cancer’s ability to proliferate and evade immune surveillance.
How the Antibody Works
Cusatuzumab is engineered to bind with high affinity to the extracellular domain of the CD70 molecule, neutralizing its activity. By attaching to the CD70 protein on the cancer cell surface, the antibody prevents CD70 from engaging its natural receptor, CD27. This blocks the aberrant CD70/CD27 signaling cascade, which is important for the survival and self-renewal of leukemia stem cells (LSCs).
Cusatuzumab is also a glyco-engineered antibody, meaning its constant region is modified to enhance interaction with immune effector cells. This modification, often achieved through defucosylation technology, improves the antibody’s ability to initiate Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). During ADCC, the antibody, bound to the cancer cell, acts as a flag, recruiting immune cells like Natural Killer (NK) cells.
The recruited NK cells recognize the flagged cell and release cytotoxic substances that destroy the malignant cell. The drug’s mechanism also includes other cell-killing processes, such as Antibody-Dependent Cellular Phagocytosis (ADCP) and Complement-Dependent Cytotoxicity (CDC). These combined immune-mediated effects eliminate cancer cells and reduce LSCs, which are often resistant to standard chemotherapy.
Diseases Targeted
Cusatuzumab’s development focuses on hematological malignancies, which are cancers affecting the blood and bone marrow. Clinical studies concentrate on treating Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS). These diseases are characterized by the rapid production of abnormal blood cells that interfere with normal development.
AML is an aggressive cancer, and CD70 expression on AML blasts makes it an attractive target. MDS are disorders where blood cells are poorly formed or dysfunctional, often progressing into AML, which justifies their inclusion in research. The drug is often studied in patients ineligible for intensive chemotherapy due to age or underlying health conditions.
Cusatuzumab is frequently administered intravenously in combination with other anti-cancer agents, such as the hypomethylating agent azacitidine. Preclinical data suggest that azacitidine can upregulate the expression of CD70 on leukemia stem cells. This synergistic effect provides a strong rationale for the combination approach, as the increased target presence enhances the effectiveness of the antibody.
Current Status in Clinical Research
Cusatuzumab has progressed through early-stage clinical trials (Phase 1 and Phase 2) to determine appropriate dosing and effectiveness. Initial Phase 1/2 trials combining the antibody with azacitidine showed encouraging activity and a manageable safety profile in patients with newly diagnosed AML who could not tolerate intensive chemotherapy. These results supported advancement into later-stage research.
The clinical development program currently includes larger, randomized Phase 2 trials, such as the CULMINATE study. These trials compare Cusatuzumab plus azacitidine against standard therapy in similar AML populations. Researchers are also investigating the drug in a triplet regimen, combining it with azacitidine and venetoclax, based on preclinical evidence suggesting synergistic activity. The results from these ongoing studies will determine the efficacy and safety data required for regulatory submissions and eventual availability.
Safety Profile and Adverse Effects
The safety profile of Cusatuzumab has been evaluated in clinical trials, both alone and in combination with other treatments. When combined with agents like azacitidine, the drug has a safety profile consistent with what is observed in this heavily treated and often frail patient population. The most common adverse events reported are related to the underlying disease and concurrent chemotherapy.
Common adverse events include hematologic toxicities, such as neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and anemia. These low counts can lead to complications like infections, including febrile neutropenia and sepsis. A specific side effect is infusion-related reactions (IRRs), which are transient events occurring during or shortly after intravenous infusion, but are manageable with standard supportive care.