PD-L1 Detection in Tumors Using [64Cu]Atezolizumab with PET
- 25 July 2016
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 27 (9), 2103-2110
- https://doi.org/10.1021/acs.bioconjchem.6b00348
Abstract
The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [64Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [64Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET-CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [64Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [64Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [64Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO-hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [64Cu]atezolizumab for the detection of PD-L1 expression in different tumor types.Keywords
Funding Information
- U.S. Department of Health and Human Services (P30 CA006973, P50 CA103175, R01CA16631)
- Johns Hopkins University
This publication has 31 references indexed in Scilit:
- Functional Imaging of Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab PETJournal of Nuclear Medicine, 2013
- Oncology Meets Immunology: The Cancer-Immunity CycleImmunity, 2013
- Evidence for a Role of the PD-1:PD-L1 Pathway in Immune Resistance of HPV-Associated Head and Neck Squamous Cell CarcinomaCancer Research, 2013
- Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 AntibodyClinical Cancer Research, 2013
- Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune EscapeScience Translational Medicine, 2012
- Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphomaBlood, 2010
- Triple-negative breast cancer: Molecular features, pathogenesis, treatment and current lines of researchCancer Treatment Reviews, 2010
- Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in gliomaNature Medicine, 2006
- Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasionNature Medicine, 2002
- Determination of the immunoreactive function of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excessJournal of Immunological Methods, 1984