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Development of 5D3-DM1: A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive
Colin T Huang1, Xin Guo2, Cyril Bařinka3
1The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, United States.
Abstract:
Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.
Insights
A new antibody-drug conjugate targeting prostate-specific membrane antigen (PSMA) effectively controlled tumor growth in mice. This novel therapy shows promise for treating aggressive prostate cancer (PC) without causing systemic toxicity.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Prostate cancer (PC) is a leading cause of cancer-related deaths in men, with advanced stages often progressing to castrate-resistant prostate cancer (CRPC).
- Current treatments for CRPC, including androgen deprivation therapy (ADT) and chemotherapy, have limitations, necessitating novel therapeutic strategies.
- Prostate-specific membrane antigen (PSMA) is highly expressed in aggressive PC and serves as a promising target for diagnostics and therapeutics.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) targeting PSMA for prostate cancer therapy.
- To assess the binding affinity, internalization, and cytotoxicity of the 5D3-DM1 ADC in vitro.
- To determine the in vivo therapeutic efficacy and toxicity of the 5D3-DM1 ADC in preclinical models of prostate cancer.
Main Methods:
- Development of an antibody-drug conjugate (ADC) using the 5D3 anti-PSMA monoclonal antibody (mAb) and mertansine (DM1).
- In vitro evaluation of the 5D3-DM1 ADC for binding affinity, internalization into PSMA-expressing cells, and cytotoxicity.
- In vivo assessment of the 5D3-DM1 ADC's efficacy in controlling tumor growth and its systemic toxicity in PSMA(+) and PSMA(-) mouse models of human PC.
Main Results:
- The 5D3-DM1 ADC demonstrated high binding affinity and efficient internalization into PSMA-expressing prostate cancer cells in vitro.
- In vivo studies showed that the 5D3-DM1 ADC significantly controlled the growth of PSMA(+) tumors.
- The anti-PSMA ADC exhibited no significant systemic toxicity in the evaluated mouse models.
Conclusions:
- The 5D3-DM1 ADC is a promising targeted therapy for PSMA-expressing prostate cancer.
- This novel ADC effectively targets and eliminates cancer cells by delivering a cytotoxic payload to the centrosome.
- The preclinical data support further development of this anti-PSMA ADC for clinical application in prostate cancer treatment.
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