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Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer

Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety...

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Main Authors: Xiaojie Chu (Author), Seungmin Shin (Author), Du-San Baek (Author), Liyong Zhang (Author), Alex Conard (Author), Megan Shi (Author), Ye-Jin Kim (Author), Cynthia Adams (Author), Maggie Hines (Author), Xianglei Liu (Author), Chuan Chen (Author), Zehua Sun (Author), Dontcho V. Jelev (Author), John W. Mellors (Author), Dimiter S. Dimitrov (Author), Wei Li (Author)
Format: Book
Published: Taylor & Francis Group, 2024-12-01T00:00:00Z.
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Summary:Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63-69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.
Item Description:10.1080/19420862.2024.2387240
1942-0870
1942-0862

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