[Cardiotoxicity of Anti-PD-L1 Antibody and the Effect of Levothyroxine 
in Attenuating the Related Mortality in Mice].

Abstract

BACKGROUND:

Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice.

METHODS:

Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 μg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 μg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 μg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 μg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse MonitorTM and non-invassive blood pressure minotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA).

RESULTS:

PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody.Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice.

CONCLUSIONS:

The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality.

• Authors: Zhenyin Chen, Min Wang, Sanhui Gao, Hua Guo, Guizhen Wang, Guangbiao Zhou
• Journal: Zhongguo fei ai za zhi = Chinese journal of lung cancer (Zhongguo Fei Ai Za Zhi) Vol. 24 Issue 6 Pg. 394-403 (Jun 20 2021) ISSN: 1999-6187 [Electronic] China
• PMID: 34157799 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• Cd274 protein, mouse
• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• Thyroid Hormones
• Thyroxine

Topics

• Animals
• B7-H1 Antigen (antagonists & inhibitors)
• Cardiotoxicity (etiology, mortality, prevention & control)
• Humans
• Immune Checkpoint Inhibitors (adverse effects)
• Mice
• Mice, Inbred C57BL
• Myocarditis (chemically induced, mortality, prevention & control)
• Programmed Cell Death 1 Receptor (metabolism)
• Thyroid Hormones (pharmacology, therapeutic use)
• Thyroxine (pharmacology, therapeutic use)