Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate.

Abstract

BACKGROUND:

Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging.

METHODS:

To study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974, 89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution.

RESULTS:

In tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes.

CONCLUSION:

[89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.

• Authors: Stijn Jh Waaijer, Danique Giesen, Takahiro Ishiguro, Yuji Sano, Naofumi Sugaya, Carolina P Schröder, Elisabeth Ge de Vries, Marjolijn N Lub-de Hooge
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (03 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32217763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Bispecific
• Antineoplastic Agents, Immunological
• CD3 Complex
• GPC3 protein, human
• Glypicans
• Radioisotopes
• bispecific antibody ERY974
• Zirconium
• Zirconium-89

Topics

• Animals
• Antibodies, Bispecific (pharmacology, therapeutic use)
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Apoptosis
• CD3 Complex (immunology)
• Carcinoma, Hepatocellular (diagnostic imaging, drug therapy, immunology, pathology)
• Cell Proliferation
• Female
• Glypicans (immunology)
• Humans
• Liver Neoplasms (diagnostic imaging, drug therapy, immunology, pathology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Positron-Emission Tomography (methods)
• Radioisotopes (chemistry)
• T-Lymphocytes (drug effects, immunology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Zirconium (chemistry)