PSMA (FOLH1) Chimeric Antigen Receptor (CAR): A Comprehensive Guide and Our Service & Product Introduction

PSMA remains the most promising target for solid tumor CAR-T therapy, with continuous technological advancements addressing existing challenges and unlocking new clinical potential. RGBiotech’s comprehensive PSMA CAR plasmid vector portfolio and custom construction services are designed to empower researchers and biotech companies to accelerate preclinical research and translational development. Whether you need ready-to-use high-quality PSMA CAR vectors or fully customized vector solutions, we provide technical support, product documentation, and after-sales assistance to ensure your research proceeds efficiently and reliably. Contact us today at admin@rgbiotech.com to discuss your PSMA CAR research project and find the optimal vector solution for your needs.

Our PSMA (FOLH1) CAR Expression Plasmid Vector Products and Custom Services

Prostate-Specific Membrane Antigen (PSMA) has emerged as one of the most validated and clinically valuable targets for solid tumor immunotherapy, especially for metastatic castration-resistant prostate cancer (mCRPC) and other PSMA-positive malignancies. Chimeric Antigen Receptor (CAR)-T cell therapy targeting PSMA has shown groundbreaking potential in overcoming the limitations of conventional treatments, with ongoing research and clinical development rapidly advancing.

RGBiotech provides a comprehensive range of PSMA CAR expression plasmid vectors covering all CAR generations, plus flexible custom vector construction services tailored to preclinical research, drug development, and academic studies. Our vectors are engineered for high expression efficiency, stable integration, and strict quality control, supporting reliable and reproducible experimental results.

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Introduction of PSMA (FOLH1)

PSMA, officially named Folate Hydrolase 1 (FOLH1), also known as Glutamate Carboxypeptidase II (GCPII), is a protein-coding gene located on the short arm of human chromosome 11 (11p11.12). The gene spans approximately 60 kb and contains 19 exons, encoding a 750-amino acid type II integral membrane glycoprotein. PSMA is highly conserved across mammalian species, highlighting its critical physiological and pathological roles. Genetic variants of FOLH1 are associated with folate metabolism disorders, neurological conditions, and prostate cancer progression risk, making it a multifunctional target beyond oncology.

PSMA adopts a distinct three-domain structural conformation as a type II transmembrane protein, with a unique topology critical for its targeting and enzymatic activity. 1) Intracellular Domain (ICD): Short 19-amino acid cytoplasmic tail, involved in intracellular signaling, cytoskeleton anchoring, and protein trafficking regulation. 2) Transmembrane Domain (TMD): 24-amino acid hydrophobic helix, stably anchoring the protein to the cell membrane lipid bilayer. 3) Extracellular Domain (ECD): Large 707-amino acid extracellular region, the primary binding site for CAR constructs, antibodies, and small-molecule ligands. This domain folds into three functional subdomains (apical, helical, protease) and forms a symmetric homodimer-dimerization is mandatory for full enzymatic activity. Post-translational modifications, including N-linked glycosylation, further stabilize the protein structure and enhance its cell surface expression, making it highly accessible for CAR-T cell recognition.

PSMA exhibits dual biological functions spanning physiological metabolism and pathological progression. 1) Enzymatic Activity: Acts as a glutamate carboxypeptidase, hydrolyzing dietary folate polyglutamates to absorbable monoglutamates, and breaking down the neuropeptide N-acetylaspartylglutamate (NAAG) in the nervous system to regulate neurotransmission. 2) Tumor-Associated Role: Promotes prostate cancer cell proliferation, invasion, metastasis, and angiogenesis; highly upregulated in hormone-refractory and metastatic prostate cancer, making it a ideal target for targeted therapy and molecular imaging.

PSMA shows a tumor-restricted high-expression pattern with minimal normal tissue expression, a key advantage for targeted therapy safety. 1) Normal Tissues: Low-level expression limited to prostate epithelium, renal proximal tubules, small intestine brush border, and rare nervous system cells; negligible expression in other vital organs. 2) Pathological Tissues: Overexpressed in ≥90% of primary prostate cancers and nearly 100% of metastatic castration-resistant prostate cancer (mCRPC); also highly expressed in tumor neovasculature of multiple solid tumors (breast, lung, bladder, renal cell carcinoma), expanding its therapeutic scope beyond prostate cancer.

PSMA is tightly linked to multiple malignant and non-malignant disorders, with oncology being the primary focus. 1) Prostate Cancer: The most well-documented indication, especially mCRPC (unmet medical need with limited standard treatments). 2) Other Solid Tumors: Tumors with PSMA-positive neovasculature, including breast cancer, non-small cell lung cancer, bladder cancer, and pancreatic cancer. 3) Neurological Disorders: Linked to neuropathic pain, schizophrenia, and Alzheimer’s disease due to its role in NAAG metabolism.

Introduction of PSMA (FOLH1) Chimeric Antigen Receptor (CAR)

PSMA CAR is a genetically engineered chimeric antigen receptor designed to specifically target the extracellular domain of PSMA, enabling T cells to recognize and eliminate PSMA-positive tumor cells independently of MHC presentation. A typical PSMA CAR construct consists of four core modules:
1) Antigen-Binding Domain: Single-chain variable fragment (scFv) derived from anti-PSMA monoclonal antibodies, mediating specific PSMA recognition.
2) Hinge/Transmembrane Region: Connects the scFv to intracellular domains, ensuring structural stability and membrane localization.
3) Co-Stimulatory Domain(s): Determines CAR generation and T cell activation potency (e.g., CD28, 4-1BB, OX40).
4) Intracellular Signaling Domain: CD3ζ chain, triggering T cell cytotoxicity and activation.

PSMA CAR constructs have evolved across multiple generations to enhance efficacy, persistence, safety, and tumor microenvironment (TME) resistance.
1) 1st Generation PSMA CAR: Only CD3ζ signaling domain, no co-stimulation; weak T cell activation, short persistence, limited clinical efficacy.
2) 2nd Generation PSMA CAR: Single co-stimulatory domain (CD28 or 4-1BB) + CD3ζ; industry standard, balanced activation and persistence—4-1BB improves long-term T cell survival, CD28 enhances rapid cytotoxicity.
3) 3rd Generation PSMA CAR: Dual co-stimulatory domains (e.g., CD28 + 4-1BB) + CD3ζ; stronger T cell proliferation and cytotoxicity, optimized for solid tumor resistance.
4) 4th Generation PSMA CAR (Armored CAR): 2nd/3rd gen backbone + transgenic cytokines (IL-12, IL-15), chemokine receptors, or immune checkpoint inhibitors (anti-PD-L1); overcomes immunosuppressive TME, boosts local anti-tumor immunity.
5) 5th Generation PSMA CAR: Integrates safety switches (suicide genes like iCasp9), antigen escape mitigation, or dual-targeting modules; enhanced safety profile, reduced off-tumor toxicity.

Key Research Achievements & Approved Therapeutics

PSMA CAR-T therapy has achieved consistent clinical responses in mCRPC, with multiple candidates in late-phase clinical trials. 1) P-PSMA-101: Phase 1 trial showed promising PSA responses and manageable safety in mCRPC patients, with high stem-cell memory T cell enrichment. 2) AUTO7: Humanized PSMA CAR-T with enhanced persistence and TME resistance, completed early-phase clinical trials with durable anti-tumor activity. 3) TGF-β-insensitive PSMA CAR-T: Overcomes TME-mediated immunosuppression, demonstrating improved efficacy in metastatic prostate cancer models.

While no PSMA CAR-T cell therapy has received full FDA/EMA approval as of 2026, multiple PSMA-targeted agents are approved, validating PSMA as a druggable target. 1) 177Lu-PSMA-617 (Pluvicto™): FDA-approved radioligand therapy for mCRPC, confirming PSMA as a highly specific and effective tumor target. 2) PSMA-targeted PET imaging agents (68Ga-PSMA-11, 18F-DCFPyL): Clinically used for prostate cancer staging and therapeutic response monitoring, critical for patient selection in PSMA CAR-T trials.

Current Research Hotspots

Research Challenges & Unmet Needs

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