With the rapid advancement of cancer immunotherapy, new agents are offering hope in cancer treatment. However, the issue of cardiotoxicity associated with these therapies is drawing increasing attention from researchers. Creative Biolabs provides a range of services for the development of cancer immunotherapeutics and the analysis of cardiotoxicity, ensuring the safety and efficacy of each drug.

Introduction

In recent years, immunotherapy drugs for tumors have emerged as a significant area in cancer treatment, leveraging the immune system to identify and attack cancer cells. However, the use of these drugs can also be associated with certain cardiac toxicities, which may pose a threat to their potential therapeutic efficacy.

Creative Biolabs offers a variety of CRO analysis services focused on assessing the cardiotoxicity of oncology immunotherapies. Our capabilities include comprehensive cardiac function monitoring, pharmacokinetic analysis, and evaluation of adverse reactions. We are committed to collaborating with you to advance the safe development of immuno-oncology drugs, ultimately providing more effective and safer treatment options.

Fig.1 Cardiotoxicity Caused by Immune Checkpoint Inhibitors.^1,3

Services

At Creative Biolabs, we typically start by identifying potential targets, such as checkpoint inhibitors (PD-1/PD-L1, CTLA-4), through high-throughput screening and bioinformatics analysis. Following this, we conduct a systematic evaluation of their efficacy and safety, including monitoring for potential cardiac toxicity.

To analyze cardiac toxicity induced by tumor immunotherapy leads, we employ a variety of methodological approaches. Initially, we develop animal models to assess changes in cardiac function post-treatment, utilizing techniques such as echocardiography or electrocardiography to capture structural and functional metrics of the heart. Furthermore, we measure biochemical markers (troponin or BNP) to evaluate the extent of cardiac injury. Histological techniques are used to observe pathological changes in cardiac tissue, coupled with molecular biology methods to investigate the direct effects of the drugs on cardiac cells and their underlying mechanisms.

Crucially, we undertake regular monitoring of the cardiac status across various preclinical biological models, collecting relevant cardiac data to more accurately assess the cardiovascular safety of cancer immunotherapies. Our services have thus far not only shed light on the mechanisms underlying cardiac toxicity but also provided critical insights for enhancing safety and advancing new drug development. With our data, we can improve the efficacy of cancer immunotherapy while minimizing its potential risks to the heart, ultimately achieving targeted and personalized cancer treatment objectives.

Fig.2 The PD-1 Inhibitor Negatively Affected Heart Function.^2,3

Case Study:

• Objectives

1. To develop a new immune drug, referred to as Drug X, and assess its anti-tumor efficacy.
2. To evaluate the cardiac toxicity of Drug X in animal models.

• Experimental Design

PART I. Drug Development

1. Compound Screening:
   - Select a variety of small molecule inhibitors targeting PD-1 expressed in tumor cells
   - Utilize MTT assays to screen for effective candidate compounds.
2. Drug Optimization:
   Conduct molecular modifications on the active compounds identified in the screening to enhance their selectivity and bioavailability.
3. Confirmation of Drug Structure:
   - Employ nuclear magnetic resonance and mass spectrometry to verify the structure of the compounds.

PART II. Assessment of Anti-cancer Efficacy

1. In Vitro Experiments:
   Use various tumor cell lines, such as MC-38 mouse colon cancer cells and A375 human melanoma cells.
   Treat the cells with Drug X at different concentrations for 48 hours, and assess apoptosis rates through flow cytometry (FACS).
2. In Vivo Experiments:
   Implant MC-38 cells in C57BL/6 mice, and initiate treatment with Drug X once tumors have formed.
   Measure tumor volume weekly to evaluate the drug's impact on tumor growth.

PART III. Evaluation of Cardiac Toxicity

1. Cardiac Function Assessment:
   Use echocardiography to evaluate cardiac function in mice, measuring parameters such as ejection fraction and ventricular wall thickness.
   Implement a 4-week treatment regimen with weekly monitoring of cardiac function.
2. Myocardial Histopathological Analysis:
   After treatment concludes, obtain cardiac tissue samples from the mice for HE and Masson staining to observe histological changes.
3. Biochemical Marker Assessment:
   Measure levels of cardiac biomarkers (such as BNP and troponin I) in serum to evaluate the extent of cardiac damage.

Creative Biolabs offers our clients extensive support throughout the drug design, screening, and preclinical phases to facilitate an expedited development process. Also, utilizing advanced technologies and a wealth of analytical techniques, we conduct systematic cardiotoxicity assessments for candidate immunotherapy leads, evaluating their potential impact on the heart to ensure drug safety. If you are working on the development of new cancer immunotherapy leads or have any questions regarding cardiotoxicity analysis, please feel free to contact us at any time!

References

1. Zito, Concetta, et al. "Cardiotoxicity induced by immune checkpoint inhibitors: what a cardio-oncology team should know and do." Cancers 14.21 (2022): 5403.
2. Xia, Wenzheng, et al. "Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling." Cell death & disease 11.7 (2020): 575.
3. Distributed under Open Access license CC BY 4.0, without modification.

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