89Zr-MSTP2109A, A Novel Antibody Based Radiotracer to Evaluate and Guide the Clinical Translation of Antibody-Drug Conjugates Targeting STEAP1

Abstract

Purpose/Objective(s)STEAP1 is a multipass transmembrane protein upregulated in multiple cancers, including prostate cancer. On this basis, a drug conjugate of MSTP2109A (a fully humanized monoclonal antibody to an extracellular epitope on STEAP1) is currently being evaluated as a therapy in advanced prostate cancer. Since the mechanisms driving the upregulation of STEAP1 in prostate cancer are complex (in some contexts, standard of care androgen deprivation therapy can suppress STEAP1 expression), we reasoned that an imaging tool to measure STEAP1 expression in patients would be essential for a systematic evaluation of this therapeutic strategy.Materials/MethodsMSTP2109A was conjugated to zirconium-89 via desferrioxamine using standard bioconjugation and radiochemistry. The binding affinity of the complex was assessed using a LINDMO assay, and the biodistribution of the radiotracer was evaluated in mouse models bearing subcutaneous prostate cancer tumors. Small animal PET imaging was performed to quantify changes in standardized uptake values.ResultsRadiolabeling MSTP2109A resulted in no dramatic reduction in binding affinity for STEAP1. 89Zr-MSTP2109A specifically localized to multiple STEAP1-positive prostate cancer tumors, and was readily blocked with excess cold antibody. Castration reduced radiotracer accumulation in CWR22Pc xenografts, a human prostate cancer model in which STEAP1 expression is controlled by the androgen receptor.ConclusionsOur preclinical data strongly supports a first in man trial with 89Zr-MSTP2109A. Moreover, the case for applying this radiotracer in prostate cancer is particularly compelling, as standard of care androgen deprivation therapies that one might think to be sensibly applied alongside the antibody-drug conjugate could potentially attenuate its effects. Purpose/Objective(s)STEAP1 is a multipass transmembrane protein upregulated in multiple cancers, including prostate cancer. On this basis, a drug conjugate of MSTP2109A (a fully humanized monoclonal antibody to an extracellular epitope on STEAP1) is currently being evaluated as a therapy in advanced prostate cancer. Since the mechanisms driving the upregulation of STEAP1 in prostate cancer are complex (in some contexts, standard of care androgen deprivation therapy can suppress STEAP1 expression), we reasoned that an imaging tool to measure STEAP1 expression in patients would be essential for a systematic evaluation of this therapeutic strategy. STEAP1 is a multipass transmembrane protein upregulated in multiple cancers, including prostate cancer. On this basis, a drug conjugate of MSTP2109A (a fully humanized monoclonal antibody to an extracellular epitope on STEAP1) is currently being evaluated as a therapy in advanced prostate cancer. Since the mechanisms driving the upregulation of STEAP1 in prostate cancer are complex (in some contexts, standard of care androgen deprivation therapy can suppress STEAP1 expression), we reasoned that an imaging tool to measure STEAP1 expression in patients would be essential for a systematic evaluation of this therapeutic strategy. Materials/MethodsMSTP2109A was conjugated to zirconium-89 via desferrioxamine using standard bioconjugation and radiochemistry. The binding affinity of the complex was assessed using a LINDMO assay, and the biodistribution of the radiotracer was evaluated in mouse models bearing subcutaneous prostate cancer tumors. Small animal PET imaging was performed to quantify changes in standardized uptake values. MSTP2109A was conjugated to zirconium-89 via desferrioxamine using standard bioconjugation and radiochemistry. The binding affinity of the complex was assessed using a LINDMO assay, and the biodistribution of the radiotracer was evaluated in mouse models bearing subcutaneous prostate cancer tumors. Small animal PET imaging was performed to quantify changes in standardized uptake values. ResultsRadiolabeling MSTP2109A resulted in no dramatic reduction in binding affinity for STEAP1. 89Zr-MSTP2109A specifically localized to multiple STEAP1-positive prostate cancer tumors, and was readily blocked with excess cold antibody. Castration reduced radiotracer accumulation in CWR22Pc xenografts, a human prostate cancer model in which STEAP1 expression is controlled by the androgen receptor. Radiolabeling MSTP2109A resulted in no dramatic reduction in binding affinity for STEAP1. 89Zr-MSTP2109A specifically localized to multiple STEAP1-positive prostate cancer tumors, and was readily blocked with excess cold antibody. Castration reduced radiotracer accumulation in CWR22Pc xenografts, a human prostate cancer model in which STEAP1 expression is controlled by the androgen receptor. ConclusionsOur preclinical data strongly supports a first in man trial with 89Zr-MSTP2109A. Moreover, the case for applying this radiotracer in prostate cancer is particularly compelling, as standard of care androgen deprivation therapies that one might think to be sensibly applied alongside the antibody-drug conjugate could potentially attenuate its effects. Our preclinical data strongly supports a first in man trial with 89Zr-MSTP2109A. Moreover, the case for applying this radiotracer in prostate cancer is particularly compelling, as standard of care androgen deprivation therapies that one might think to be sensibly applied alongside the antibody-drug conjugate could potentially attenuate its effects.