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Target Overview
STEAP2 (six-transmembrane epithelial antigen of the prostate 2) is a six transmembrane receptor that functions as a metalloreductase to reduce copper and iron to forms that facilitate cellular metabolism and proliferation.1,2 STEAP2 is an attractive therapeutic target owing to its limited normal tissue expression that is largely restricted to prostate epithelia, abundant expression across all stages of prostate cancer, and potential use as a diagnostic marker due to its correlation with Gleason score. 3,4 In prostate cancer, STEAP2 overexpression is associated with more aggressive disease by promoting cell proliferation, migration, and invasion, indicating that it may not be easily dispensable as a means of resistance. 2-6
Compound Overview
AZD0516 is a novel investigational antibody drug conjugate (ADC) that consists of an anti-STEAP2 human IgG1 monoclonal antibody conjugated via interchain cysteines to a β-glucuronidase-cleavable maleimide linker bearing the topoisomerase 1 inhibitor payload, exatecan (AZD7588), at a drug-antibody ratio of 8. The antibody component of AZD0516 binds to STEAP2 on the surface of prostate cancer cells, thereby promoting internalization and trafficking of the ADC to the lysosome. Enzymatic cleavage of the linker by β-glucuronidase releases the exatecan payload, which stabilizes topoisomerase-DNA cleavage complexes at replication forks, leading to the formation of DNA double-strand breaks (DSBs). If unrepaired, the DSBs ultimately lead to programmed cell death. Exatecan is also capable of diffusing through cell membranes of STEAP2-positive cells to target neighboring tumor cells that do not express STEAP2, causing cell death via a bystander effect.
Mechanism of Action
References
1. Ohgami RS, Campagna DR, McDonald A, Fleming MD. Blood. 2006;108(4):1388-1394. 2. Wang L, Jin Y, Arnoldussen YJ, et al. Cancer Res. 2010;70(14):5818-5828. 3. Burnell SEA, Spencer-Harty S, Howarth S, et al. PLoS One. 2019;14(8):e0220456. 4. Ylitalo EB, Thysell E, Jernberg E, et al. Eur Urol. 2017;71(5):776-787. 5. Burnell SEA, Spencer-Harty S, Howarth S, et al. Sci Rep. 2018;8(1):6252. 6. Jones LA, Conway GE, Nguyen-Chi A, et al. Cell Mol Biol. 2023;69(4):179-187.
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Abbreviations
ADC
antibody drug conjugate
DNA
deoxyribonucleic acid
DSBs
double-strand breaks
mCRPC
metastatic castration-resistant prostate cancer
STEAP2
six-transmembrane epithelial antigen of the prostate-2
Target Overview
STEAP2 (six-transmembrane epithelial antigen of the prostate 2) is a six transmembrane receptor that functions as a metalloreductase to reduce copper and iron to forms that facilitate cellular metabolism and proliferation.1,2 STEAP2 is an attractive therapeutic target owing to its limited normal tissue expression that is largely restricted to prostate epithelia, abundant expression across all stages of prostate cancer, and potential use as a diagnostic marker due to its correlation with Gleason score. 3,4 In prostate cancer, STEAP2 overexpression is associated with more aggressive disease by promoting cell proliferation, migration, and invasion, indicating that it may not be easily dispensable as a means of resistance. 2-6
Compound Overview
AZD0516 is a novel investigational antibody drug conjugate (ADC) that consists of an anti-STEAP2 human IgG1 monoclonal antibody conjugated via interchain cysteines to a β-glucuronidase-cleavable maleimide linker bearing the topoisomerase 1 inhibitor payload, exatecan (AZD7588), at a drug-antibody ratio of 8. The antibody component of AZD0516 binds to STEAP2 on the surface of prostate cancer cells, thereby promoting internalization and trafficking of the ADC to the lysosome. Enzymatic cleavage of the linker by β-glucuronidase releases the exatecan payload, which stabilizes topoisomerase-DNA cleavage complexes at replication forks, leading to the formation of DNA double-strand breaks (DSBs). If unrepaired, the DSBs ultimately lead to programmed cell death. Exatecan is also capable of diffusing through cell membranes of STEAP2-positive cells to target neighboring tumor cells that do not express STEAP2, causing cell death via a bystander effect.
Mechanism of Action
References
1. Ohgami RS, Campagna DR, McDonald A, Fleming MD. Blood. 2006;108(4):1388-1394. 2. Wang L, Jin Y, Arnoldussen YJ, et al. Cancer Res. 2010;70(14):5818-5828. 3. Burnell SEA, Spencer-Harty S, Howarth S, et al. PLoS One. 2019;14(8):e0220456. 4. Ylitalo EB, Thysell E, Jernberg E, et al. Eur Urol. 2017;71(5):776-787. 5. Burnell SEA, Spencer-Harty S, Howarth S, et al. Sci Rep. 2018;8(1):6252. 6. Jones LA, Conway GE, Nguyen-Chi A, et al. Cell Mol Biol. 2023;69(4):179-187.
Clinical trial information
Select trial for more information
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Abbreviations
ADC
antibody drug conjugate
DNA
deoxyribonucleic acid
DSBs
double-strand breaks
mCRPC
metastatic castration-resistant prostate cancer
STEAP2
six-transmembrane epithelial antigen of the prostate-2