What is the PSMA target?
Prostate-specific membrane antigen (PSMA) is a protein found on the surface of both normal and cancerous prostate cells. However, its expression is significantly higher on malignant prostate cells, particularly in advanced and hormone-refractory prostate cancer. This makes PSMA an ideal target for therapeutic agents that can selectively home in on cancer cells while sparing normal tissue to a great extent. PSMA is a transmembrane protein with a large portion of it extending outside the cell, which is easily accessible to drug molecules. This external domain is a key binding site for the antibodies used in PSMA-targeted therapies. Beyond its role as a biomarker, PSMA also plays a biological role in promoting prostate cancer development, suggesting that targeting it can interrupt cancer-fueling pathways.
How does a PSMA antibody drug work?
PSMA-targeted therapies use a 'homing device'—either a monoclonal antibody or a small molecule—to deliver a toxic payload specifically to cancer cells. This category includes both antibody-drug conjugates (ADCs) and radioligand therapies (RLTs).
Mechanism of Antibody-Drug Conjugates (ADCs)
ADCs are biopharmaceutical drugs designed to deliver cytotoxic agents directly to cancer cells. A PSMA-targeting ADC works through a multi-step process:
- Target Recognition: The monoclonal antibody component of the ADC is engineered to recognize and bind to the extracellular domain of PSMA on the surface of prostate cancer cells.
- Internalization: After binding, the entire ADC-PSMA complex is taken inside the cancer cell through a process called receptor-mediated endocytosis.
- Payload Release: Once inside the cell, the ADC is trafficked to the lysosomes, where enzymes cleave a special linker that connects the antibody to the cytotoxic drug.
- Cell Death: The potent cytotoxic agent is released into the cell, where it disrupts essential cellular processes, such as microtubule assembly, leading to cell cycle arrest and apoptosis (programmed cell death).
This targeted delivery mechanism minimizes the systemic exposure of the toxic drug, thereby reducing damage to healthy, non-cancerous tissues.
Mechanism of Radiolabeled Antibody Therapy (RLT)
In radioligand therapy, the PSMA-targeting molecule is labeled with a radioactive isotope, such as Lutetium-177 or Actinium-225. The mechanism is similar to ADCs but uses radiation for its cytotoxic effect:
- Targeting and Binding: The radiolabeled antibody binds specifically to PSMA on cancer cells.
- Radiation Delivery: Once bound, the radioactive isotope emits radiation directly to the targeted cancer cells. Beta-emitters like Lutetium-177 have a longer range and are effective for larger tumors, while alpha-emitters like Actinium-225 have a shorter range and higher energy, ideal for smaller or disseminated tumors.
- DNA Damage: The radiation damages the DNA of the cancer cells, leading to cell death.
Approved and Investigational PSMA antibody drugs
Several PSMA-targeted therapies have been approved by the FDA, while others are in clinical development. For instance, Lutetium-177-PSMA-617 (Pluvicto) is an FDA-approved radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). It is important to note that while Pluvicto uses a PSMA-targeting small molecule, antibody-based approaches like the radiolabeled J591 antibody (investigational) have also been extensively studied. ADCs like ARX517 have received FDA Fast Track designation for mCRPC, signaling promising results in clinical trials. Other emerging therapies include bispecific T-cell engagers (BiTEs) that bind to both PSMA on cancer cells and CD3 on T cells to trigger an immune response.
Comparison of PSMA-targeted therapies
While all PSMA-targeted therapies aim to deliver a cytotoxic payload specifically to cancer cells, they differ in their structure, delivery mechanism, and side effect profile. A key distinction is between ADCs and RLTs, and further between small-molecule and antibody-based RLTs.
| Feature | Antibody-Drug Conjugates (ADCs) | Small-Molecule Radioligand Therapy (e.g., Lu-177 PSMA-617) | Antibody-Based Radioligand Therapy (e.g., Lu-177 J591) |
|---|---|---|---|
| Homing Molecule | Monoclonal Antibody | Small Molecule | Monoclonal Antibody |
| Payload | Cytotoxic chemotherapy agent (e.g., MMAE) | Radioactive isotope (β- or α-emitter) | Radioactive isotope (β- or α-emitter) |
| Circulation Time | Longer | Shorter | Longest |
| Clearance | Slower | Rapid (mostly via kidneys) | Slowest |
| Salivary Gland Exposure | Minimal | Moderate-high | Minimal |
| Bone Marrow Toxicity | Generally higher with slower clearance | Lower due to rapid clearance | Higher due to prolonged circulation |
| Key Target Site | PSMA on cancer cell surface | PSMA on cancer cell surface | PSMA on cancer cell surface |
Potential side effects
The side effect profile of PSMA-targeted therapy is influenced by the specific agent used. Common adverse events for radioligand therapy like Pluvicto can include fatigue, nausea, dry mouth (xerostomia), and myelosuppression (low blood counts). Xerostomia often occurs because PSMA is expressed in the salivary glands, leading to off-target radiation exposure. For ADCs, toxicities can include neutropenia and peripheral neuropathy. Ongoing research focuses on mitigating these side effects, for example, by using radioprotective agents.
The future of PSMA-targeted therapies
Researchers are continually refining and expanding PSMA-targeted therapies. Future directions include exploring these treatments earlier in the disease course, potentially in combination with other standard therapies. Trials are investigating combining PSMA radioligands with other systemic treatments like immunotherapy or androgen receptor pathway inhibitors to potentially increase efficacy and overcome resistance. New formulations of PSMA-targeted agents and improved half-life extension methods are also being developed to broaden patient access and improve treatment outcomes. The field is moving towards a more personalized, multimodal approach that integrates PSMA-based treatments into comprehensive care plans. For additional resources on prostate cancer research, the National Cancer Institute is an authoritative source.
National Cancer Institute is a leading source for information on targeted cancer therapies.
