Publication

Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue

Giesen, D., Broer, L. N., Lub-de Hooge, M. N., Popova, I., Howng, B., Nguyen, M., Vasiljeva, O., de Vries, E. G. E. & Pool, M., 17-Jan-2020, In : Clinical Cancer Research. 40 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Giesen, D., Broer, L. N., Lub-de Hooge, M. N., Popova, I., Howng, B., Nguyen, M., ... Pool, M. (2020). Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-19-3137

Author

Giesen, Danique ; Broer, Linda N ; Lub-de Hooge, Marjolijn N ; Popova, Irina ; Howng, Bruce ; Nguyen, Margaret ; Vasiljeva, Olga ; de Vries, Elisabeth G E ; Pool, Martin. / Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue. In: Clinical Cancer Research. 2020.

Harvard

Giesen, D, Broer, LN, Lub-de Hooge, MN, Popova, I, Howng, B, Nguyen, M, Vasiljeva, O, de Vries, EGE & Pool, M 2020, 'Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-19-3137

Standard

Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue. / Giesen, Danique; Broer, Linda N; Lub-de Hooge, Marjolijn N; Popova, Irina; Howng, Bruce; Nguyen, Margaret; Vasiljeva, Olga; de Vries, Elisabeth G E; Pool, Martin.

In: Clinical Cancer Research, 17.01.2020.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Giesen D, Broer LN, Lub-de Hooge MN, Popova I, Howng B, Nguyen M et al. Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue. Clinical Cancer Research. 2020 Jan 17. https://doi.org/10.1158/1078-0432.CCR-19-3137


BibTeX

@article{c1e58602e0cc4a34908a950c6f6ce617,
title = "Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue",
abstract = "PURPOSE: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr).EXPERIMENTAL DESIGN: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis.RESULTS: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design.CONCLUSIONS: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development (NCT03013491).",
author = "Danique Giesen and Broer, {Linda N} and {Lub-de Hooge}, {Marjolijn N} and Irina Popova and Bruce Howng and Margaret Nguyen and Olga Vasiljeva and {de Vries}, {Elisabeth G E} and Martin Pool",
note = "Copyright {\circledC}2020, American Association for Cancer Research.",
year = "2020",
month = "1",
day = "17",
doi = "10.1158/1078-0432.CCR-19-3137",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "AMER ASSOC CANCER RESEARCH",

}

RIS

TY - JOUR

T1 - Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue

AU - Giesen, Danique

AU - Broer, Linda N

AU - Lub-de Hooge, Marjolijn N

AU - Popova, Irina

AU - Howng, Bruce

AU - Nguyen, Margaret

AU - Vasiljeva, Olga

AU - de Vries, Elisabeth G E

AU - Pool, Martin

N1 - Copyright ©2020, American Association for Cancer Research.

PY - 2020/1/17

Y1 - 2020/1/17

N2 - PURPOSE: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr).EXPERIMENTAL DESIGN: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis.RESULTS: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design.CONCLUSIONS: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development (NCT03013491).

AB - PURPOSE: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr).EXPERIMENTAL DESIGN: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis.RESULTS: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design.CONCLUSIONS: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development (NCT03013491).

U2 - 10.1158/1078-0432.CCR-19-3137

DO - 10.1158/1078-0432.CCR-19-3137

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -

ID: 112489843