ADCs – New developing ways for innovative treatments

The ADCs or better known as Antibody-drug conjugates are cytotoxic drugs conjugated to a humanized monoclonal antibody directed to antigens overexpressed on a tumor cell’s surface. Intended to deliver a cytotoxic effect selectively to a tumor, the main purpose is to improve the clinical benefit and minimize the toxicity of traditional chemotherapy.

Right now, as far as we know, two clinical trials have published results regarding ACDcs targeting ES-SCLS and one of them is the next one that we are going to talk about in the next paragraphs:

  • Rovalpituzumab tesirine (Rova-T).

Rova-T is a humanized anti-DLL2 monoclonal antibody and a DNA-damaging pyrrolobenzodiazepine dimer toxin (PBD). In a specific SCLC patient model, this antibody induces durable tumor regression over 4 months and is capable to inhibit cells (TICs) compared to the activity of chemotherapy treatments. A phase I clinical trial was recently completed, in which this antibody was used to treat recurrent SCLC.

Using the next generation sequencing, scientists could notice mutations in two genes: TP53 and RB1, which were observed in nearly all SCLC subjects. Specifically, mutations in RB1 are highly associated with elevated expression of ASCL1 (Achaetescute complex homolog 1), that is a transcription factor that plays a pivotal role in neuroendocrine differentiation and correlates with tumor-initiating capacity. By using the genome microarray, scientists were able to find that DLL3 is transcriptionally regulated downstream of the ASCL1. DLL3 is one of the mammalian Notch pathway family ligands, predominantly localized in the Golgi apparatus. Notch pathway acts as anti-oncogenic stimulus in SCLC in which DLL3 interacts with Notch 1 and DLL1 in the Golgi apparatus, redirecting them for destruction and thereby preventing them reaching the cell surface where they can activate Notch signaling in trans. That’s why DLL3 could be a potential target for ADCs due to its overexpression in neuroendocrine tumor cells.

Knowing that, Saunders and colleagues established an ADC Rova-T, to target DLL3+ tumor cells. The promising results are the next: Rova-T led to an ORR in 11 of 60 evaluable patients, mPFS of 2.8 months, mOS of 4.6 months and 1-year survival rate. This result provided strong support for further investigation not only using this antibody, also for looking for other potential targets. At least, the DLL3 expression level can work as a biomarker that should promote the development of subsequent clinical trials.

This is one of the many examples that the Oncology research field show us about the importance of the clinical trials. We can do many tests in animal models, but it would not fully replace a human model. We have so many pathways that are connected, and just a single malfunction of one of those genes involved, could lead to the regulation of the expression levels of other genes.

Here in Althian, we have plenty experience managing oncology trials. We are aware about how important is to understand the protocol and what the pharmaceutical needs. Reach us and we will be more than happy to run your next clinical trial, with a complete team needed to run a successful clinical trial.