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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2387240 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576600401510400 |
|---|---|
| author | Xiaojie Chu Seungmin Shin Du-San Baek Liyong Zhang Alex Conard Megan Shi Ye-Jin Kim Cynthia Adams Maggie Hines Xianglei Liu Chuan Chen Zehua Sun Dontcho V. Jelev John W. Mellors Dimiter S. Dimitrov Wei Li |
| author_facet | Xiaojie Chu Seungmin Shin Du-San Baek Liyong Zhang Alex Conard Megan Shi Ye-Jin Kim Cynthia Adams Maggie Hines Xianglei Liu Chuan Chen Zehua Sun Dontcho V. Jelev John W. Mellors Dimiter S. Dimitrov Wei Li |
| author_sort | Xiaojie Chu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1f085d6811ce4dcda8bde14f50a5302f |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-1f085d6811ce4dcda8bde14f50a5302f2025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2387240Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancerXiaojie Chu0Seungmin Shin1Du-San Baek2Liyong Zhang3Alex Conard4Megan Shi5Ye-Jin Kim6Cynthia Adams7Maggie Hines8Xianglei Liu9Chuan Chen10Zehua Sun11Dontcho V. Jelev12John W. Mellors13Dimiter S. Dimitrov14Wei Li15Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USAGLPG, Pittsburgh, PA, USAHillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USAGLPG, Pittsburgh, PA, USAComputational and System Biology, School of Medicine, University of Pittsburgh, Pittsburgh, USAGLPG, Pittsburgh, PA, USAGLPG, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USAGLPG, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USACenter for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USAProstate 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.https://www.tandfonline.com/doi/10.1080/19420862.2024.2387240Antibody drug conjugatefully human antibodymonomethyl auristatin Eprostate cancerPSCAtumor xenograft mouse model |
| spellingShingle | Xiaojie Chu Seungmin Shin Du-San Baek Liyong Zhang Alex Conard Megan Shi Ye-Jin Kim Cynthia Adams Maggie Hines Xianglei Liu Chuan Chen Zehua Sun Dontcho V. Jelev John W. Mellors Dimiter S. Dimitrov Wei Li Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer mAbs Antibody drug conjugate fully human antibody monomethyl auristatin E prostate cancer PSCA tumor xenograft mouse model |
| title | Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer |
| title_full | Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer |
| title_fullStr | Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer |
| title_full_unstemmed | Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer |
| title_short | Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer |
| title_sort | discovery of a novel highly specific fully human psca antibody and its application as an antibody drug conjugate in prostate cancer |
| topic | Antibody drug conjugate fully human antibody monomethyl auristatin E prostate cancer PSCA tumor xenograft mouse model |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2387240 |
| work_keys_str_mv | AT xiaojiechu discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT seungminshin discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT dusanbaek discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT liyongzhang discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT alexconard discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT meganshi discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT yejinkim discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT cynthiaadams discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT maggiehines discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT xiangleiliu discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT chuanchen discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT zehuasun discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT dontchovjelev discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT johnwmellors discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT dimitersdimitrov discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer AT weili discoveryofanovelhighlyspecificfullyhumanpscaantibodyanditsapplicationasanantibodydrugconjugateinprostatecancer |