PMID- 31953313
OWN - NLM
STAT- MEDLINE
DCOM- 20211101
LR  - 20211101
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 26
IP  - 15
DP  - 2020 Aug 1
TI  - Probody Therapeutic Design of (89)Zr-CX-072 Promotes Accumulation in 
      PD-L1-Expressing Tumors Compared to Normal Murine Lymphoid Tissue.
PG  - 3999-4009
LID - 10.1158/1078-0432.CCR-19-3137 [doi]
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 PET 
      isotope zirconium-89 ((89)Zr). EXPERIMENTAL DESIGN: (89)Zr-labeled CX-072, 
      nonspecific 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 after intravenous injection (pi), followed by ex vivo 
      biodistribution. Intratumoral (89)Zr-CX-072 distribution was studied by 
      autoradiography on tumor tissue sections, which were subsequently stained for 
      PD-L1 by IHC. Activated CX-072 species in tissue lysates were detected by Western 
      capillary electrophoresis. RESULTS: PET imaging revealed (89)Zr-CX-072 
      accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 
      days pi compared with (89)Zr-PbCtrl. Tumor tissue autoradiography showed high 
      (89)Zr-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, (89)Zr-CX-072 uptake by lymphoid tissues of immune-competent mice 
      bearing MC38 tumors was low compared with (89)Zr-CX-075, which lacks the Probody 
      design. CONCLUSIONS: (89)Zr-CX-072 accumulates specifically in PD-L1-expressing 
      tumors with limited uptake in murine peripheral lymphoid tissues. Our data may 
      enable clinical evaluation of (89)Zr-CX-072 whole-body distribution as a tool to 
      support CX-072 drug development (NCT03013491).
CI  - (c)2020 American Association for Cancer Research.
FAU - Giesen, Danique
AU  - Giesen D
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, Groningen, the Netherlands.
FAU - Broer, Linda N
AU  - Broer LN
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, Groningen, the Netherlands.
FAU - Lub-de Hooge, Marjolijn N
AU  - Lub-de Hooge MN
AUID- ORCID: 0000-0002-5390-2791
AD  - Department of Clinical Pharmacy and Pharmacology, University Medical Center 
      Groningen, University of Groningen, Groningen, the Netherlands.
AD  - Department of Nuclear Medicine and Molecular Imaging, University Medical Center 
      Groningen, University of Groningen, Groningen, the Netherlands.
FAU - Popova, Irina
AU  - Popova I
AD  - CytomX Therapeutics, Inc., South San Francisco, California.
FAU - Howng, Bruce
AU  - Howng B
AD  - CytomX Therapeutics, Inc., South San Francisco, California.
FAU - Nguyen, Margaret
AU  - Nguyen M
AUID- ORCID: 0000-0003-0878-5896
AD  - CytomX Therapeutics, Inc., South San Francisco, California.
FAU - Vasiljeva, Olga
AU  - Vasiljeva O
AUID- ORCID: 0000-0003-3648-5460
AD  - CytomX Therapeutics, Inc., South San Francisco, California. 
      ovasiljeva@cytomx.com.
FAU - de Vries, Elisabeth G E
AU  - de Vries EGE
AUID- ORCID: 0000-0002-8949-7425
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, Groningen, the Netherlands. ovasiljeva@cytomx.com.
FAU - Pool, Martin
AU  - Pool M
AD  - Department of Medical Oncology, University Medical Center Groningen, University 
      of Groningen, Groningen, the Netherlands.
LA  - eng
SI  - ClinicalTrials.gov/NCT03013491
PT  - Journal Article
DEP - 20200117
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Radioisotopes)
RN  - 0 (Radiopharmaceuticals)
RN  - C6V6S92N3C (Zirconium)
RN  - NTM296JU95 (Zirconium-89)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage/chemistry/*pharmacokinetics
MH  - Autoradiography
MH  - B7-H1 Antigen/*antagonists & inhibitors
MH  - Cell Line, Tumor
MH  - Drug Design
MH  - Humans
MH  - Immune Checkpoint Inhibitors/administration & dosage/chemistry/*pharmacokinetics
MH  - Male
MH  - Mice
MH  - Neoplasms/diagnostic imaging/*drug therapy/immunology/pathology
MH  - Positron-Emission Tomography
MH  - Radioisotopes/administration & dosage/chemistry/pharmacokinetics
MH  - Radiopharmaceuticals/administration & dosage/chemistry/*pharmacokinetics
MH  - Tissue Distribution
MH  - Tumor Microenvironment/drug effects/immunology
MH  - Xenograft Model Antitumor Assays
MH  - Zirconium/administration & dosage/chemistry/pharmacokinetics
EDAT- 2020/01/19 06:00
MHDA- 2021/11/03 06:00
CRDT- 2020/01/19 06:00
PHST- 2019/09/25 00:00 [received]
PHST- 2019/11/26 00:00 [revised]
PHST- 2020/01/14 00:00 [accepted]
PHST- 2020/01/19 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2020/01/19 06:00 [entrez]
AID - 1078-0432.CCR-19-3137 [pii]
AID - 10.1158/1078-0432.CCR-19-3137 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2020 Aug 1;26(15):3999-4009. doi: 10.1158/1078-0432.CCR-19-3137. 
      Epub 2020 Jan 17.