Antibody-Drug and other protein-drug Conjugates to Fight Glioblastoma Multiforme
Here we are at the thirteenth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is chapter 9 of the guide. I would like to finish the translation of the guide by the end of this month so that we can group all these posts into a single publication which will also be downloadable from this website. In this episode we talk about drug-antibody (ABT-414) and drug-protein (MDNA55) conjugates. The advice is still to use this information to discuss it with the medical team that is following you. You can also point them to references to supporting scientific works.
I ask you once again to help the fundraising campaign Glioblastoma.it for CUSP-ND for Emanuele at least by sharing the link in order to spread the word and raise awareness as many people as possible. Enjoy the reading!
ABT-414 is a drug-antibody conjugate targeting EGFR overexpressing cells. ABT-414 consists of an antibody (ABT-806) bound to a microtubule-targeted cytotoxin, called monomethyl auristatin F. The antibody binds to EGFR only when it is in the active conformation, thus selectively targeting tumor cells that express the ‘EGFR and minimizing the effects on healthy tissue.
The safety, dose determination and efficacy results from a phase 1 multicenter study were published at the end of 2016 (361). This phase 1 study did not require patients to have EGFR amplification, and only 39% of 38 patients had EGFR amplification in tumors. Eye toxicity, especially blurred vision, was the most common side effect, occurring in 89% of 45 patients.
In the exploratory analysis for antitumor activity, the median progression-free survival (PFS) for all patients (n = 45) was 6.1 months. The median PFS for all patients with amplified EGFR (n = 15) was 5.9 months.
The median progression-free survival observed in this study does not reflect an improvement over standard treatments, although the authors caution that caution should be used in evaluating efficacy parameters in this phase I study, given the varying doses administered, the number of Study drug discontinuations due to toxicity, small sample sizes, and numerous confounding prognostic factors that may contribute to the observed PFS and OS measurements.
The experimental drug of Medicenna MDNA55 is a fusion of a truncated form of interleukin 4 (IL-4) with the bacterial exotoxin A of Pseudomonas. The toxin is only active inside the cell after absorption through the interleukin 4 receptors (IL-4R). Therefore this therapy targets cells with high IL-4R expression, which is common in tumor tissue and myeloid-derived suppressor cells, but rare in normal brain tissue, thus sparing healthy cells. The drug is infused directly into the tumor via Convection Enhanced Delivery.
Preliminary data released by Medicenna on their website show that the drug has surprising efficacy in early phase trials for recurrent malignant gliomas. In one study, in which 25 patients with recurrent glioblastoma were treated with a single infusion of MDNA55 and no resection, the response rate was 56%, the complete response rate was 20%, and the response rate with disease stabilization was 68%. These response and complete response rates are among the highest reported for recurrent glioblastoma, where response rates are typically less than 20% and complete response rates are less than 5%.
(361) Reardon, David A., et al. “Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma.” Neuro-Oncology, 2016, doi:10.1093/neuonc/now257.
Fine! I hope you enjoyed reading, I was as faithful as possible. Soon the next chapter! See you soon!