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Target Overview
Prostate-Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein that is present in all prostatic tissues and is overexpressed in prostate cancer cells.1 It is a glutamate carboxypeptidase II enzyme and encoded by the human FOLH1 (folate hydrolase 1) gene. PSMA expression is associated with disease progression and worse clinical outcomes.2,3,4
Compound Overview
Actinium (225Ac) zadavotide guraxetan (AZD2265) is a PSMA targeting radioconjugate (also known as 225Ac-PSMA-I&T) designed for metastatic castration-resistant prostate cancer. It consists of three parts: 1) a moiety that binds to PSMA, 2) a linker, and 3) a chelator that acts as a “cage” to hold radioactive isotopes, like actinium-225. PSMA-I&T was optimized for high PSMA affinity, fast pharmacokinetics, and high metabolic stability as described in Weineisen et al.5
(225Ac) Zadavotide guraxetan binds with high affinity to PSMA on the surface of prostate cancer cells. The radioactive decay of actinium-225 (and subsequent daughter isotopes) leads to alpha particle emission, which results in significant DNA and cellular damage and apoptotic cell death.
Mechanism of Action
References
1. Chang SS. Rev Urol. 2004;6 Suppl 10(Suppl 10):S13-S18. 2. Minner S, Wittmer C, Graefen M, et al. Prostate. 2011;71(3):281–288. 3. Vlachostergios PJ et al. Front Oncol. 2021;11:630589. 4. Hupe MC, Philippi C, Roth D, et al. Front Oncol. 2018;8:623. 5. Weineisen M et al. J Nucl Med. 2015;56(8):1169-1176.
Target Overview
Prostate-Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein that is present in all prostatic tissues and is overexpressed in prostate cancer cells.1 It is a glutamate carboxypeptidase II enzyme and encoded by the human FOLH1 (folate hydrolase 1) gene. PSMA expression is associated with disease progression and worse clinical outcomes.2,3,4
Compound Overview
Actinium (225Ac) zadavotide guraxetan (AZD2265) is a PSMA targeting radioconjugate (also known as 225Ac-PSMA-I&T) designed for metastatic castration-resistant prostate cancer. It consists of three parts: 1) a moiety that binds to PSMA, 2) a linker, and 3) a chelator that acts as a “cage” to hold radioactive isotopes, like actinium-225. PSMA-I&T was optimized for high PSMA affinity, fast pharmacokinetics, and high metabolic stability as described in Weineisen et al.5
(225Ac) Zadavotide guraxetan binds with high affinity to PSMA on the surface of prostate cancer cells. The radioactive decay of actinium-225 (and subsequent daughter isotopes) leads to alpha particle emission, which results in significant DNA and cellular damage and apoptotic cell death.
Mechanism of Action
References
1. Chang SS. Rev Urol. 2004;6 Suppl 10(Suppl 10):S13-S18. 2. Minner S, Wittmer C, Graefen M, et al. Prostate. 2011;71(3):281–288. 3. Vlachostergios PJ et al. Front Oncol. 2021;11:630589. 4. Hupe MC, Philippi C, Roth D, et al. Front Oncol. 2018;8:623. 5. Weineisen M et al. J Nucl Med. 2015;56(8):1169-1176.
Clinical trial information
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AlphaBreak trial overview
PROSPECTOR trial overview
VECTRA-01 trial overview
Abbreviations
Ac
actinium
FOLH1
folate hydrolase 1
I&T
Imaging & Therapy
mCRPC
metastatic castration-resistant prostate cancer
PSMA
prostate-specific membrane antigen