What are the therapeutic candidates targeting PSMA?

Introduction to PSMA

Prostate‐specific membrane antigen (PSMA) is a type II transmembrane glycoprotein endowed with significant enzymatic functions. It plays a critical biological role by exhibiting dipeptidase activity (cleaving γ-linked glutamates from poly-γ-glutamyl folate) and proteolytic activity on substrates such as N-acetyl-L-aspartyl-L-glutamate (NAAG). This dual functionality may contribute to processes such as neuronal signal transduction as well as folate metabolism in the small intestine. In addition to its physiological roles in the brain and intestine, PSMA’s most notable feature is its strong expression in prostate epithelial cells, especially in malignant tissues. The extraordinary upregulation of PSMA—in some cases up to 1000-fold higher levels compared to normal prostate cells—has been established through numerous histopathological and biochemical studies.

Biological Role and Expression

PSMA is expressed not only in the normal prostate epithelium, where it is usually confined to the cytoplasmic and apical regions, but also in various non-prostatic tissues. However, its expression in non-prostatic tissues, such as the salivary glands, renal tubules, and small intestinal brush border, is minimal relative to that seen in prostate cancer cells. In the transformation from benign to malignant prostate tissue, PSMA gradually relocates from the cytoplasm to the cell membrane, rendering its large extracellular domain accessible for ligand binding—a process that underlies its suitability as a therapeutic target. Furthermore, PSMA is localized in the neovasculature of several solid tumors, including renal cell carcinomas, colon, esophageal, thyroid, lung, and brain cancers; however, it is largely absent from the vasculature of normal tissues. This unique expression pattern not only signifies its key biological roles but also creates a therapeutic window where targeting PSMA can allow for the selective delivery of diagnostic and therapeutic agents to tumor cells while sparing normal tissues.

Importance in Prostate Cancer

PSMA is of central importance in the diagnosis and treatment of prostate cancer. Its overexpression is considered a marker of aggressive disease and is correlated with tumor dedifferentiation, metastasis to lymph nodes and bone, and castration-resistance. Owing to its membrane localization and high binding potential, PSMA has emerged as the most widely used molecular target for both diagnostic imaging and therapeutic interventions in prostate cancer. The high sensitivity and specificity of PSMA-targeted imaging agents have revolutionized prostate cancer staging and restaging, thereby enabling personalized treatment decisions. PSMA has, in many ways, become synonymous with the theranostic concept—a combined therapeutic and diagnostic approach—leading to the development of numerous therapeutic candidates that exploit its unique overexpression in prostate tumors.

Therapeutic Candidates Targeting PSMA

Therapeutic strategies targeting PSMA leverage its unique biological features to deliver various drugs and radionuclides selectively to prostate cancer cells. The therapeutic candidates are classified mainly into three broad categories: small molecule inhibitors, monoclonal antibodies, and radioligand therapies. Each category follows a tailored mechanism of action and displays distinct pharmacokinetic profiles. In this section, we discuss these candidates from multiple perspectives, highlighting the diversity of approaches, the intricate design considerations, and the translational pathways that have been developed, as evidenced by numerous preclinical and clinical studies.

Small Molecule Inhibitors

Small molecule inhibitors designed to target PSMA are typically low–molecular weight compounds that mimic either the natural substrate or the transition state of the PSMA enzyme. They are engineered with a binding motif, such as the glutamate-urea-based structure, which confers high affinity and selectivity to PSMA. Prominent examples of such compounds include 18F-DCFPyL, 18F-PSMA-1007, PSMA I&T, and PSMA-617.

Small molecule PSMA inhibitors are usually radiolabeled for diagnostic imaging or therapeutic purposes. For example, 18F-DCFPyL is used in positron emission tomography (PET) imaging to detect prostate cancer lesions with high sensitivity, due to its rapid pharmacokinetics and excellent tumor-to-background uptake ratios. Similarly, 18F-PSMA-1007 has been noted for its superior image quality compared to its 68Ga-based counterparts, largely due to its minimal urinary excretion that facilitates the detection of pelvic lesions.

Another significant candidate from this class is PSMA-617. This molecule is designed with a potent binding motif and a chelator that can be complexed with various therapeutic radionuclides, such as lutetium-177 (177Lu), making it useful for radioligand therapy (RLT) as well as imaging, when complexed with gallium-68 (68Ga). PSMA I&T is another optimized PSMA inhibitor that has shown promising preclinical and clinical results in both diagnostic and therapeutic applications, thanks to its favorable biodistribution and rapid internalization in PSMA-positive cells. These small molecules are characterized by their ease of synthesis, rapid clearance from the blood, and strong tumor penetration – attributes that have propelled them into the forefront of targeted prostate cancer therapeutics.

Monoclonal Antibodies

Monoclonal antibodies (mAbs) represent a different therapeutic modality, focusing on larger, protein-based molecules that can bind specifically and with high affinity to the extracellular domain of PSMA. One of the earliest and best studied examples is the humanized mAb J591. Unlike earlier agents such as capromab pendetide (ProstaScint™), which bind to intracellular epitopes and thus are limited in their diagnostic and therapeutic utility, J591 targets the extracellular domain of PSMA, allowing for effective binding to viable tumor cells.

Monoclonal antibodies such as J591 have been extensively conjugated with various payloads, including radionuclides for radioimmunotherapy. For instance, J591 has been labeled with 177Lu for therapeutic applications and with 89Zr for PET imaging. Other approaches have involved the development of antibody fragments (such as scFvs) which offer advantages like faster blood clearance and improved tumor penetration over full-length antibodies. The high specificity of these mAbs not only facilitates their use in imaging but also in delivering cytotoxic agents directly to tumor cells. Research into these candidates continues to evolve with efforts to balance the long circulatory half-life of intact antibodies against the need for rapid clearance to minimize off-target effects.

Radioligand Therapies

Radioligand therapies (RLTs) exploit the targeting capability of PSMA ligands by coupling them to radioactive isotopes. The binding and subsequent internalization of the ligand–PSMA complex within tumor cells facilitate the localized delivery of ionizing radiation, which damages tumor DNA and induces cell death.

Among the most notable radioligand therapies, 177Lu-PSMA-617 stands out as a frontrunner. Lutetium-177 emits beta particles that induce cytotoxicity while its half-life enables practical clinical application. 177Lu-PSMA-617 has demonstrated significant benefits in patients with metastatic castration-resistant prostate cancer (mCRPC), as evidenced by improvements in progression-free and overall survival in major clinical trials. Similarly, 225Ac-PSMA, which employs actinium-225 – an alpha emitter – offers a higher linear energy transfer and a shorter tissue range, potentially making it more effective in eradicating microscopic disease while reducing collateral damage to adjacent healthy tissues.

Other candidates include PSMA-targeted thorium conjugates such as the PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), which have been evaluated preclinically for their potent antitumor efficacy. In addition, novel complexes such as 212Pb-NG001 have been designed to harness alpha particle emissions using lead-212, thereby offering therapeutic options for resistant tumors. These radioligand therapy candidates are continually optimized in terms of chelator design, isotope selection, and dosing regimens to maximize therapeutic benefits while minimizing renal and salivary gland toxicities, which are common adverse effects due to off-target uptake.

Development and Clinical Trials

The development pipeline for PSMA-targeted therapeutics has grown exponentially over the last two decades, driven by the clear link between PSMA expression and prostate cancer aggressiveness. Advances in molecular imaging, drug design, and radionuclide chemistry have converged to yield a rich portfolio of candidates in preclinical and clinical evaluation.

Current Development Pipeline

The current development pipeline is robust, encompassing both small molecules and antibody-based therapeutics. On the small molecule front, compounds such as 18F-DCFPyL, 18F-PSMA-1007, PSMA I&T, and PSMA-617 have completed several phase I and II trials, with some, most notably 177Lu-PSMA-617, advancing to phase III studies. The design of these agents involves iterative structural modifications to optimize binding affinity, pharmacokinetics, and dosimetric properties. Recent studies have focused on modifying the linker and chelator segments to enhance tumor uptake and minimize renal retention, as demonstrated by the development of next-generation PSMA inhibitors with improved imaging and therapeutic indices.

In parallel, monoclonal antibodies targeting PSMA have also evolved from early prototypes to more refined constructs such as J591, which is now under evaluation in both therapeutic and imaging contexts. Novel antibody formats, including single-chain variable fragments (scFvs) and antibody–drug conjugates, are being investigated to overcome limitations like long half-life and limited tumor penetration associated with full-length antibodies.

Radioligand therapies represent the most advanced and clinically impactful category within the pipeline. 177Lu-PSMA-617 is a flagship candidate, now approved in several regions and showing promise in improving median progression-free survival in mCRPC patients. Concurrently, alpha emitters such as 225Ac-PSMA and PSMA-TTC are undergoing preclinical and early phase clinical evaluations. These agents are being tested not only as monotherapies but also in combination with other systemic treatments, such as androgen deprivation therapy and chemotherapy, to effectively address resistance and improve outcomes.

Key Clinical Trial Results

The clinical trial landscape has been rich with studies evaluating the efficacy and safety of PSMA-targeted therapies. One of the most pivotal trials, the VISION trial, enrolled patients with mCRPC and demonstrated that treatment with 177Lu-PSMA-617 significantly prolonged progression-free and overall survival compared with standard care. These impressive results have cemented the role of radioligand therapy in later-line treatment settings and spurred further trials to investigate earlier intervention strategies.

Another important study was the TheraP trial, which, by employing both PSMA-PET and FDG-PET imaging for patient selection, underscored the importance of molecular imaging in tailoring PSMA-targeted therapies. This trial confirmed high response rates as indicated by dramatic PSA declines and radiographic responses. Early phase trials evaluating 225Ac-PSMA have reported promising antitumor activity with manageable toxicity profiles; however, challenges such as salivary gland toxicity remain a focus of ongoing research.

Monoclonal antibodies like J591, when conjugated with radionuclides such as 177Lu or 89Zr, have also been assessed in phase I/II trials. These studies have provided critical insights into dosimetry, pharmacokinetics, and off-target effects, leading to refinements in antibody engineering and dosing strategies. Additionally, the evolving pipeline includes trials combining different PSMA-targeted agents with conventional therapies, aiming to enhance therapeutic efficacy through synergistic mechanisms. The diverse clinical trial portfolio reflects the multi-pronged effort to optimize PSMA-targeted treatments, with each modality contributing unique advantages in terms of efficacy, safety, and patient selection.

Challenges and Future Directions

The rapid pace of discovery in PSMA-targeted therapies is not without its challenges. Despite substantial progress, several obstacles remain that must be addressed to fully realize the potential of these agents.

Current Challenges

One of the predominant challenges is the heterogeneity of PSMA expression among patients and even within different tumor sites in the same patient. This intrapatient and interpatient heterogeneity can lead to variable responses to therapy and challenges in patient selection, as demonstrated by imaging studies that show mixed PSMA expression patterns across lesions. Additionally, while radioligand therapies such as 177Lu-PSMA-617 have shown clear clinical benefits, off-target uptake in organs such as the kidneys and salivary glands can lead to adverse effects like nephrotoxicity and xerostomia. These toxicities necessitate the development of protective strategies (such as amino acid infusions) and further modifications to the ligand structure to minimize non-specific uptake.

Furthermore, the long circulatory half-life and slow tumor penetration associated with monoclonal antibodies pose a limitation for rapid and effective targeting. Although engineered antibody fragments and alternative formats are emerging, optimizing their stability and binding affinity remains a complex task. In the arena of small molecule inhibitors, the challenge lies in achieving the ideal balance between sufficient tumor retention and rapid clearance from non-target tissues. The complex interplay of these factors impacts both the diagnostic quality of imaging agents and the therapeutic efficacy of radioligand therapies.

There are also regulatory and logistical hurdles in designing and implementing well-powered, multicenter clinical trials that incorporate advanced imaging biomarkers for patient selection. The need for precise quantification of PSMA expression and standardization of imaging protocols across sites has been emphasized in several recent publications, reflecting the challenges of translating promising preclinical findings into consistent clinical benefits.

Future Prospects and Research Directions

Looking forward, the future of PSMA-targeted therapies is promising, with several research directions that may help overcome current challenges. Advances in molecular imaging technologies are expected to further refine patient selection processes, ensuring that only those with high, homogeneous PSMA expression receive targeted therapies. Integrating new imaging biomarkers and standardizing protocols will enhance the reliability of PSMA-PET, thereby improving treatment outcomes.

Ongoing efforts aim to modify the ligand structures of small molecule inhibitors to further boost their tumor uptake while reducing renal and salivary gland retention. Research into the molecular determinants of PSMA internalization could enable the design of ligands that are more efficiently internalized and retained within cancer cells, thus increasing the delivered radiation dose to the tumor.

For monoclonal antibodies, the development of bispecific antibodies or antibody–drug conjugates is under active investigation. These constructs aim to leverage the high specificity of antibodies while mitigating the drawbacks of long blood residence times. Furthermore, combining PSMA-targeted agents with other therapies, such as androgen receptor inhibitors, chemotherapy, or immunotherapy, represents a promising approach to overcome resistance mechanisms and broaden the therapeutic impact. Combination therapy strategies will be increasingly guided by detailed genomic and proteomic profiling to identify patient subgroups that stand to benefit most from multi-agent regimens.

In radioligand therapies, there is an active pursuit of next-generation agents that employ alpha emitters (e.g., 225Ac, 212Pb) to deliver more potent and localized cytotoxic radiation. Alpha emitters, by virtue of their high linear energy transfer, can potentially overcome resistance observed with beta emitters by inducing double-strand DNA breaks with greater efficiency. However, the optimization of dosage and the minimization of collateral damage to normal tissues remain critical areas of research.

Additional innovative avenues include the development of theranostic platforms that not only treat the tumor but also provide real-time feedback on treatment efficacy via integrated imaging. The vision of a truly personalized approach, where therapeutic decisions are refined based on dynamic imaging and biomarker feedback, is driving the design of adaptive clinical trials that combine targeted therapies with conventional treatment modalities.

Finally, the emergence of combined modality therapies, such as antibody–radioconjugate combinations and multimodal treatment regimens, is expected to expand further the therapeutic landscape of PSMA-targeted therapy. Efforts to mitigate toxicity through protective agents and improved ligand design will be central to these advances. With ongoing advancements, the ultimate goal is to improve patient outcomes by extending survival, preserving quality of life, and reducing the side effects associated with current PSMA-targeted therapies.

Conclusion

In summary, the therapeutic candidates targeting PSMA span a broad and diverse spectrum that includes small molecule inhibitors, monoclonal antibodies, and radioligand therapies. PSMA’s unique biological characteristics and its marked overexpression in prostate cancer have driven the development of these candidates, which serve both diagnostic and therapeutic purposes. Small molecule inhibitors such as 18F-DCFPyL, 18F-PSMA-1007, PSMA I&T, and PSMA-617 are at the forefront of molecular imaging and radioligand therapy due to their rapid clearance and high tumor penetration. Monoclonal antibodies like J591 provide high specificity and have enabled the targeted delivery of radionuclides and cytotoxic agents, though challenges related to tissue penetration and half-life remain. Radioligand therapies employing beta emitters (e.g., 177Lu-PSMA-617) and alpha emitters (e.g., 225Ac-PSMA, PSMA-TTC, 212Pb-NG001) have demonstrated promising clinical outcomes, particularly in patients with advanced castration-resistant prostate cancer, while also highlighting the need to manage off-target toxicities.

The development and clinical trials over the past two decades have reinforced the efficacy of these approaches, as evidenced by landmark studies such as the VISION and TheraP trials. Nonetheless, significant challenges persist, including heterogeneity in PSMA expression, off-target toxicities in organs such as kidneys and salivary glands, and the difficulty in achieving optimal pharmacokinetics for various therapeutic modalities. Future research is therefore geared toward refining ligand design, incorporating advanced imaging for precise patient selection, and integrating PSMA-targeted therapies with other treatment strategies to overcome resistance mechanisms.

In conclusion, the field of PSMA-targeted therapeutics represents an exciting convergence of molecular biology, nuclear medicine, and precision oncology. While significant challenges remain, continued advancements in the design of small molecules, antibodies, and radioligand therapies are poised to transform the management of prostate cancer. The strategic incorporation of these agents into personalized treatment plans, guided by robust imaging and biomarker data, promises to enhance clinical outcomes and improve quality of life for patients with advanced prostate cancer. As the pipeline continues to evolve, collaboration between researchers, clinicians, and industry will be paramount to overcoming current obstacles and ensuring that the full promise of PSMA targeting is realized in the clinic.