Enoblituzumab is an investigational immunotherapy for cancer. It is a humanized monoclonal antibody, a laboratory-produced antibody designed to mimic the body’s natural antibodies and specifically target certain proteins. This therapy is currently undergoing clinical trials to assess its safety and effectiveness in treating various cancers, aiming to harness the body’s own immune system to fight the disease.
How Enoblituzumab Works
Enoblituzumab functions by targeting a protein called B7-H3, which is often found in high amounts on the surface of various cancer cells. B7-H3 is a member of the B7 family of immune checkpoint molecules, and its presence on tumor cells typically acts as a “brake” on the immune system, preventing immune cells, particularly T-cells, from recognizing and attacking the cancer. By binding to B7-H3, enoblituzumab effectively blocks this immune-suppressing signal.
This blockade reactivates T-cells and other immune effector cells, enhancing the body’s immune response against cancer cells. Enoblituzumab also incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain, which further enhances its anti-tumor activity by promoting antibody-dependent cellular cytotoxicity (ADCC). This process recruits other immune cells, such as natural killer cells and macrophages, to destroy the cancer cells.
In addition to its direct action on B7-H3, enoblituzumab is being investigated for its potential in combination with other immune checkpoint inhibitors, such as pembrolizumab, which targets the PD-1 receptor on T-cells. Combining these therapies is hypothesized to provide a more comprehensive immune response, as enoblituzumab addresses B7-H3-mediated immune suppression, while pembrolizumab enhances T-cell activation through a different pathway. This dual targeting approach aims to maximize anti-tumor activity by engaging both innate and adaptive arms of the immune system.
Cancers Targeted by Enoblituzumab
Enoblituzumab is being investigated for cancers with high B7-H3 expression, including prostate cancer, sarcoma, and ovarian cancer. The significant overexpression of B7-H3 on these tumor cells makes them susceptible to enoblituzumab’s mechanism of action.
For prostate cancer, enoblituzumab has been studied in a phase 2 neoadjuvant trial for intermediate to high-risk localized disease, evaluating treatment before surgery. Other cancers explored in trials include non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, and bladder cancer, often in combination with other immunotherapies.
These investigations span various phases of clinical development. Initial phase 1 studies evaluated enoblituzumab as a monotherapy and in combination with other checkpoint inhibitors across a broad range of solid tumors to assess safety and preliminary activity. Subsequent trials, like the phase 1/2 study combining enoblituzumab with pembrolizumab, further explored its use in advanced solid tumors, including specific cohorts for NSCLC and HNSCC.
Clinical Trial Findings
Clinical trials of enoblituzumab provide insights into its efficacy and safety. In a phase 2 neoadjuvant study for localized intermediate- to high-risk prostate cancer, 32 patients received weekly infusions before radical prostatectomy. The study reported 66% of participants had no detectable prostate-specific antigen (PSA) levels one year after surgery, indicating no signs of residual disease.
Regarding safety, this prostate cancer trial showed enoblituzumab was well-tolerated. Overall, 12% of patients experienced grade 3 adverse events, with no grade 4 events. Common side effects in earlier phase 1 studies included infusion-related reactions and fatigue, which were mild to moderate and manageable with supportive care.
In a phase 1/2 study combining enoblituzumab with pembrolizumab in advanced solid tumors, treatment-related adverse events occurred in 87.2% of 133 patients, with 28.6% experiencing grade 3 or higher events. One treatment-related death due to pneumonitis was reported. Objective responses were observed in checkpoint inhibitor-naïve HNSCC (33.3% response rate, 6 of 18 patients) and checkpoint inhibitor-naïve NSCLC (35.7% response rate, 5 of 14 patients). Enoblituzumab is administered as an intravenous infusion.