Targeting Advanced Prostate Cancer with Anti-PSMA Antibodies

PSMA (prostate-specific membrane antigen) is over-expressed on the membrane of aggressive prostate cancer (PCa) cells, and as such has been found to be a promising target for the treatment of advanced PCa. The use of a PSMA-targeted antibody is a growing area of research.

What is PSMA?

Primarily housed on the surface of prostate cells, PSMA is an accessible target for imaging and anti-cancer treatments. Because this protein is often overexpressed in aggressive PCa cells, it is a promising therapeutic target for patients with more advanced disease who have relapsed on previous lines of therapy. PSMA is expressed in up to 95% of prostate cancer, with a strong correlation between disease severity and expression level.

In addition to acting as a target for treatment and imaging, PSMA also serves several other important roles in prostate cancer. The expression of this antigen extends to cancer that has metastasized in lymph nodes and bone, which offers further utility for targeted therapy and diagnostic imaging.

“The possible diagnostic and therapeutic role of PSMA continues to evolve,” wrote Sam S. Chang, MD, in a review. “In prostate cancer, PSMA continues to be a useful antigenic target that will continue to be of diagnostic and therapeutic value as newer targeting agents are developed and imaging systems and techniques continue to improve. In addition, beyond prostate cancer, PSMA might represent a unique angiogenic target for a variety of neoplasms.”

PSMA Structure and Role

PSMA is a transmembrane protein that is expressed across all types of prostatic tissue. This protein has a three-part structure comprising an internal portion of 19 amino acids, a transmembrane portion of 24 amino acids, and an external portion of 707 amino acids. The PSMA gene is located on the short arm of chromosome 11 and is in a region not commonly deleted in prostate cancer. This protein has enzymatic functions and acts as a glutamate-preferring carboxypeptidase.

PSMA vs. PSA

Prostate-specific antigen (PSA) is a secretory protein that differs from PSMA in several ways. PSA, which can be detected with a blood test, is involved in the liquefaction of semen and is a known indicator of PCa. PSA has been found to decrease with androgen deprivation, which is a common hormone therapy for PCa. In contrast, PSMA activity was found to increase in prostate cancer cell lines as cells became more androgen-independent.

Treating PCa with a PSMA-Targeted Antibody

Targeted antibodies are a class of cancer immunotherapy treatment that send signals to the immune system to kill cancer cells. Antibodies are naturally produced proteins that target and bind to antigens on the cell surface.

There are now several types of targeted antibodies being researched for cancer treatment, including

  • Monocolonal antibodies (mAbs), which target tumor cells rather than immune cells
  • Antibody-drug conjugates (ADCS), which combines targeted antibodies with anti-cancer drugs
  • Bispecific antibodies, which can bind to two different targets

Researchers have developed several antibodies that are targeted at PSMA to eliminate prostate cancer cells. The first anti-PSMA antibody was the mAb 7E11, which recognized and bound a PSMA intracellular or cytoplasmic epitope. Newer antibodies have been developed to bind at different locations, such as the extracellular portion of PSMA. Additionally, recent PSMA antibodies are either fully immune or humanized, as opposed to murine antibodies.

Advancements in Anti-PSMA Antibody Therapeutics

Drugs that target PSMA in prostate cancer cells using antibodies are still currently in development. Another mAb that has been studied in PCa is J591, which has been coupled with various therapeutic radionuclides, such as Lutetium-177, Yttrium-90, Indium-111, and Actinium-225. J591 has also been studied as part of antibody-drug conjugates, including MLN2704 and PSMA-ADC.

Several anti-PSMA ADCs have been evaluated in clinical trials, including MEDI3726, which binds to PSMA and releases anti-cancer pyrrolobenzodiazepine dimer toxins to trigger cell death. In a phase I study, 33 patients with relapsed metastatic castration-resistant PCa received MEDI3726 after a median of four prior lines of treatment. The researchers noted clinical responses to treatment at higher doses, however, toxicity persists, and durability of higher dosages was not feasible. ARX517, another anti-PSMA ADC, is currently being tested in a phase I dose-escalation trial of patients with PSMA expressing tumors in prostate, pancreatic, lung, and ovarian cancers.

Additionally, in an ongoing study, REGN5678, an anti-PSMA bispecific antibody, is being assessed in combination with an anti-PD-1 antibody for patients with metastatic castration-resistant PCa. REGN5678 was developed to target both PSMA and the costimulatory receptor CD28, a protein expressed on T cells. In this phase I/II first-in-human study, researchers assessed the safety, tolerability, and anti-tumor activity of REGN5678 alone and in combination with cemiplimab.

“PSMA targeting antibodies are very promising for further clinical investigation and continue to be a momentous research area, for both imaging and therapeutic settings,” wrote Roumeguère, et al., in a recent editorial published in Current Opinion in Oncology. “Although some clinical trials resulted in unfavorably safety profiles for some antibodies, they validated PSMA as a crucial immunoconjugate target.”

How PSMA Is Detected

The primary method for detecting the presence of PSMA in prostate cancer cells is via positron emission tomography (PET) imaging. These images detect lesions that are PSMA-positive.

PSMA PET Scan

The United States Food and Drug Administration has approved the radioactive imaging agents 68Ga-PSMA-11 and piflufolastat F 18 for the use of imaging PSMA-positive lesions in men with prostate cancer. This agent binds to prostate cancer cells to help localize the cells.

When patients undergo PSMA PET imaging, they receive an injection of the radioactive tracer drug, and the PET scan can detect the concentrated tracer, which has bound to the cancer cells. Locating PSMA-positive lesions using PET imaging is a more effective and precise strategy for localizing metastatic cancer cells.

Who Should Consider PSMA PET Scan?

Individuals with an initial diagnosis of prostate cancer, who are at risk for metastatic disease or who have been previously treated and have developed biochemical recurrence may consider undergoing PSMA PET imaging.

 

References:

https://www.crescendobiologics.com/wp-content/uploads/2020/05/CrescendoBiologicsMcGuinnessHarold-May2020.pdf

https://journals.lww.com/co-oncology/Fulltext/2021/09000/Antibodies_targeting_Prostate_Specific_Membrane.16.aspx

https://www.nature.com/articles/s41391-021-00394-5?proof=tr

https://meetinglibrary.asco.org/record/194886/abstract

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472940/

https://www.mskcc.org/news/psma-new-target-prostate-cancer-treatment

https://www.cancerresearch.org/en-us/immunotherapy/treatment-types/targeted-antibodies

https://www.businesswire.com/news/home/20210803005135/en/Ambrx-Announces-First-Patient-Dosed-in-a-Phase-1-Trial-for-ARX517-an-ADC-in-Development-to-Treat-PSMA-Expressing-Tumors

https://radiology.ucsf.edu/psma-pet-scan-for-prostate-cancer