Skip to main content Skip to megamenu (after main content)
Meet us next:   ELRIG UK 2025 – 20 March  ●  IBD Innovate 2025 – 9-10 April  ●  NIH Spring Vendor Exhibit 2025 – 24 April  ●  AACR Annual Meeting 2025 – 27-30 April  ●  ISCT Conference 2025 – 7-9 May  ●  more on our events calendar

The Power of Human Tissue Models in Preclinical Research

By Ella Cutter, Digital Marketing Manager, REPROCELL Europe

This blog is the second in a series exploring the critical role of safety pharmacology in drug discovery. In our previous post, we discussed the importance of human tissue studies in ensuring drug safety. Today, we’ll dive into real-world case studies that highlight our innovative approaches and successes in utilizing human tissue models for safety assessment, demonstrating how these models have impacted drug development outcomes.  

Case Study 1: International Partnership for Microbicides (IPM) – HIV Prevention 

The International Partnership for Microbicides (IPM) was working on a groundbreaking HIV prevention product using the antiretroviral drug Dapivirine in the form of a vaginal ring (DPV-VR). As part of their regulatory process, the European Medicines Agency (EMA) requested additional studies to evaluate the potential effects of the ring on organs close to the application site, particularly the uterus. 

In 2014, IPM approached REPROCELL (Biopta) to conduct a study using fresh uterine tissue to assess whether Dapivirine affected uterine contractility. Using an organ bath study, our team tested fresh uterine muscle strips from five human donors. These muscle strips spontaneously contract and relax in organ baths, providing an ideal model for detecting any changes in uterine contractility. 

The results showed that Dapivirine had no significant effect on uterine contraction when compared to positive (oxytocin) and negative (forskolin) controls. This outcome was promising, as it suggested that DPV-VR would not cause uterine contractility issues in users. The study played a small but crucial role in the development of DPV-VR, which received a positive opinion from the EMA in 2020, offering women a new option for HIV prevention. 

Dapivarine figure 1

Figure 1: Graphs showing the effect of cumulative concentrations of vehicle, dapivirine, oxytocin and forskolin on spontaneous contraction in human uterine muscle strips. The addition of oxytocin had no effect on the peak area, however oxytocin caused an increase in the frequency of contractions (A)** = p< 0.01, *** = p<0.001 when compared to vehicle by two-way ANOVA with bonferroni post hoc test. Data expressed as mean ± SEM. N=5. (B) In the presence of 200 nM oxytocin. *** = p<0.001 when compared to vehicle by two-way ANOVA with bonferroni post hoc test. Data expressed as mean ± SEM. N=5.

Case Study 2: Amgen – Addressing Headaches in Clinical Trials 

Amgen was developing a combination therapy for solid tumors, with a promising drug candidate, AMG 337. AMG 337 is a selective inhibitor of the proto-oncogene c-Met, which plays a key role in tumor growth and drug resistance. However, during clinical trials, participants experienced headaches as a dose-limiting side effect.  

To understand the cause, REPROCELL conducted studies comparing the effects of AMG 337 on canine blood vessels, which had been used in Amgen’s preclinical studies, to human blood vessels. The canine studies had underestimated the drug’s impact on blood vessels, leading to an inaccurate prediction of side effects in humans. 

By using fresh human arteries, we were able to provide a more accurate estimate of the drug’s effects, highlighting the limitations of relying solely on animal models. This case demonstrates the value of human tissue models in preclinical research, allowing for better prediction of potential side effects in humans and helping Amgen refine their approach to dosage and safety. 

amgen case studyFigure 2: Relaxation response of AMG 337 (shown as % relaxation) in precontracted dog (A) and human (B) blood vessels. Blue, Vehicle; Black, AMG 33. Adapted from Amouzadeh et al, 2019.

Case Study 3: Roche – Understanding Diarrhea in Breast Cancer Therapy 

Roche was developing a combination therapy for breast cancer using lumretuzumab, an investigational anti-HER3 therapy, and pertuzumab, an approved anti-HER2 therapy. During clinical trials, some participants experienced severe diarrhea, which could not be relieved by traditional treatments like loperamide. This side effect became so severe that it restricted the therapeutic window, ultimately leading to the discontinuation of the therapy’s development. 

To investigate the cause, Roche collaborated with REPROCELL to study the drug’s effects on human gastrointestinal tissue. Using fresh colonic mucosa in Ussing chambers, our team examined various combinations of the drugs and concentrations, assessing ion transport to uncover the root cause of the diarrhea. The experiments revealed that the combination of therapies caused an upregulation of chloride channels in the colon, which led to increased fluid secretion and chronic diarrhea. 

Armed with this knowledge, Roche was able to recommend the use of chloride channel blockers for patients experiencing this side effect, providing a strategy to mitigate the adverse reactions. This case demonstrates how human tissue models can provide invaluable insights into the mechanisms behind side effects, ultimately improving drug safety and guiding clinical strategies. 

 Calcium activated chloride transport

Figure 3: Graphs showing the effects of pertuzumab and lumretuzumab, alone and in combination, on the plateau response of cAMP-induced chloride transport via forskolin in tissues that have been exposed to heregulin for 20 minutes where indicated. 

These case studies illustrate the critical role that human tissue models play in ensuring drug safety and efficacy. By offering more accurate, human-relevant data, these models allow pharmaceutical companies to address potential issues early in development, saving time, resources, and, most importantly, improving patient outcomes. 

Subscribe to receive updates from REPROCELL