Novartis' PSMA targeted therapy has been approved, and Bayer, Amgen, etc. are all under development. What is the development prospect of PSMA?

On March 24, Novartis announced that the U.
S.
FDA has approved the company’s targeted radioligand therapy Pluvicto (lutetium Lu 177 vipivotide tetraxetan, formerly known as 177Lu-PSMA-617 ) for the treatment of PSMA-positive metastatic disease.
Patients with castration-resistant prostate cancer (mCRPC) who have been treated with taxane-based chemotherapy and androgen receptor signaling pathway inhibitors
.

According to public information, this is the first targeted radioligand therapy approved by the FDA for the treatment of such mCRPC patients, and the approval of this drug also means another important progress in the field of PSMA targeted therapy

Targeted Radioligand Therapy Pluvicto 177Lu-PSMA-617 is the first FDA-approved targeted radioligand therapy for the treatment of such mCRPC patients.

Antibody-drug conjugates (ADCs), bispecific T cell adaptor proteins , dual antibodies, CAR-T cell therapy, etc.

Studies have shown that PSMA is overexpressed on the surface of more than 90% of prostate cancer cells (100-1000 times higher than normal prostate cells) , and the expression level is higher in cancer cells of advanced and castration-resistant prostate cancer patients
.

In addition, the neovascular endothelial cells of various tumors also highly express PSMA.

PSMA is overexpressed on the surface of more than 90% of prostate cancer cells (100-1000 times higher than normal prostate cells) .

Important targets for radioligand therapy

Prostate cancer is a radiation-sensitive tumor
.

One of the mainstays of cancer treatment, radiotherapy kills cancer cells while damaging healthy cells, with serious side effects

Attach radioisotopes to molecules capable of binding to tumor-specific antigens, increasing the accumulation of radiotracers inside cancer cells and enhancing the therapeutic effect

▲Schematic diagram of the mechanism of action of RLT (Image source: POINTBiopharma official website)

▲Schematic diagram of the mechanism of action of RLT (Image source: POINTBiopharma official website)

After continuous screening and iteration, scientists have identified a variety of ligands that can effectively bind to PSMA, most of which are small molecule compounds such as PSMA-617, PSMA-I&T, MIP-1072, MIP-1095, etc.
Cellular excretion reduces radiation exposure
.

The most widely used radioisotopes are lutetium 177 (177Lu), iodine 131 (131I), actinium 225 (225Ac), thorium 227 (227TH), radium 223 (223RA) and so on

They are rapidly excreted by cells, reducing radiation exposure

Bispecific T cell adaptor protein (BiTE) recruits T cells to the vicinity of tumor cells, thereby killing tumor cells .
The acapatamab developed based on this platform is a BiTE therapy TriTAC (trispecific T cell activation construct) antibody that targets PSMA.

▲Schematic diagram of the mechanism of action of REGN5678 (Image source: Reference [7]) Since PSMA is widely and highly expressed in tumors and low or no expression in healthy tissues , it is also an ideal target for the development of ADC therapy
.

At present, a number of ADCs targeting PSMA have entered clinical research.

▲Schematic diagram of the mechanism of action of REGN5678 (Image source: Reference [7]) The dawn of CAR-T cell therapy that is widely and highly expressed in tumors, low or no expression in healthy tissues ? This is because it is difficult to find a specific target that is only expressed in tumors and not in healthy tissue .

Poseida's PSMA-targeted CAR-T cell therapy P-PSMA-101 is intended to be developed for the treatment of solid tumors
.

A total of 9 mCRPC patients were treated in the Phase 1 clinical trial, and these patients had received an average of 6 lines of prior therapy
.
The results showed: 1 patient (received the lowest dose) showed complete tumor elimination and maintained durable remission for more than 5 months; 5 patients showed a significant decrease in the tumor marker PSA level; 3 patients showed a decrease in PSA level of more than 50%, PSMA-PET imaging consistently improved
.
In addition, this product has demonstrated a good safety profile and tolerability
.
In addition, a number of CAR-T cell therapies targeting PSMA developed by Chinese companies or research institutions have also entered Phase 1 or Phase 2 clinical trials
.
According to the official website of ClinicalTrials, the 4SCAR-PSMAT cells of Shenzhen Institute
of Immunogene Therapy are undergoing Phase 1/2 clinical trials .
According to the official website of the institute, 4SCAR is the fourth-generation CAR-T developed by the institute with a safe withdrawal mechanism.
By integrating multiple costimulatory factors and suicide genes, it not only has a significant improvement in efficacy, but also improves Safe
.
In addition, Shanghai Bangyao Bio 's PD1-PSMA-CART cells and LIGHT-PSMA-CART cells are both undergoing Phase 1 clinical research on prostate cancer
.

1 patient with CAR-T cell therapy P-PSMA-101 (received the lowest dose) showed complete tumor elimination and maintained durable remission for more than 5 months; Shanghai Bangyao Biotechnology , Shenzhen Institute of Immunogene Therapy

It is hoped that with the progress of research, different types of therapies targeting PSMA can achieve more progress and breakthroughs, benefiting more patients as soon as possible
.

References:

References:

[1] Zhang, Hanbo et al.
(2021).
PSMA Theranostics: CurrentLandscape and Future Outlook.
Cancers.
doi:10.
3390/cancers13164023

[1] Zhang, Hanbo et al.
(2021).
PSMA Theranostics: CurrentLandscape and Future Outlook.
Cancers.
doi:10.
3390/cancers13164023

[2] Ng TSC, et al.
(2021) Incorporating PSMA-Targeting Theranostics Into Personalized Prostate Cancer Treatment: aMultidisciplinary Perspective.
FrontOncol.
doi:10.
3389/fonc.
2021.
722277[3]Czerwińska, M.
et al.
(2020).
TargetedRadionuclide Therapy of Prostate Cancer-From Basic Research to ClinicalPerspectives.
Molecules.
doi:10.
3390/molecules25071743[4]POINT Biopharma Announces Initiation of Randomization for its Phase 3 SPLASH study Evaluating PNT2002 for mCRPC.
Retrieved Sep23.
2021,from https:// com/press-releases/point-biopharma-announces-initiation-of-randomization-for-its-phase-3-splash-study-evaluating-pnt2002-for-mcrpc[5] Amgen to Acquire Micromet.
Retrieved Jan 25, 2012 , from https://#:~:text=Amgen%20%28NASDAQ%3AAMGN%29%20and%20Micromet%2C%20Inc.
%20%28NASDAQ%3AMITI%29%20today%20announced,Rockville%2C%20Md.
%2C%20for%20%2411%20per%20share%20in%20cash.
[6]Bayer Acquires Noria and PSMATherapeutics to Expand Pipeline in Prostate Cancer .
Retrieved June 3,2021.
from https:// REGN ASCO 2020.
Retrieved June, 2020, from https://investor.
regeneron.
com/static- files/533336ff-6bed-40db-9a60-d58e07eec082

[2] Ng TSC, et al.
(2021) Incorporating PSMA-Targeting Theranostics Into Personalized Prostate Cancer Treatment: aMultidisciplinary Perspective.
FrontOncol.
doi:10.
3389/fonc.
2021.
722277[3]Czerwińska, M.
et al.
(2020).
TargetedRadionuclide Therapy of Prostate Cancer-From Basic Research to ClinicalPerspectives.
Molecules.
doi:10.
3390/molecules25071743[4]POINT Biopharma Announces Initiation of Randomization for its Phase 3 SPLASH study Evaluating PNT2002 for mCRPC.
Retrieved Sep23.
2021,from https:// com/press-releases/point-biopharma-announces-initiation-of-randomization-for-its-phase-3-splash-study-evaluating-pnt2002-for-mcrpc[5] Amgen to Acquire Micromet.
Retrieved Jan 25, 2012 , from https://#:~:text=Amgen%20%28NASDAQ%3AAMGN%29%20and%20Micromet%2C%20Inc.
%20%28NASDAQ%3AMITI%29%20today%20announced,Rockville%2C%20Md.
%2C%20for%20%2411%20per%20share%20in%20cash.
[6]Bayer Acquires Noria and PSMATherapeutics to Expand Pipeline in Prostate Cancer .
Retrieved June 3,2021.
from https:// REGN ASCO 2020.
Retrieved June, 2020, from https://investor.
regeneron.
com/static- files/533336ff-6bed-40db-9a60-d58e07eec082