Researchers from the Vall d’Hebron Institute of Oncology (VHIO) and Peptomyc S.L. have published results of a pharmacokinetic analysis of Omomyc, a therapeutic mini-protein that targets the MYC oncogene, which is often deregulated in human cancers.
The study, published in the journal Cancers, found that Omomyc maintained its structural integrity in tumour tissue for at least 72 hours following administration, showing longer-lasting structural integrity in tumour tissue compared to blood. This is an important finding, as the proper function of therapeutic proteins is dependent on their lasting structural integrity in the target tissue.
The success of the first Omomyc-derived compound, OMO-103, in phase I clinical trial last year is encouraging, as it had few side effects and was tolerable, and was able to stabilise disease in some patients. These results provide further validation for Omomyc as the first direct inhibitor of MYC.
Omomyc is a first-in-class MYC inhibitor that targets the MYC oncogene which is deregulated in most tumour types. This therapeutic mini-protein was developed in-house by the Vall d’Hebron Institute of Oncology (VHIO) and the Catalan Institute of Research and Advanced Studies (ICREA) spin-off company Peptomyc S.L. which was co-founded by VHIO’s Laura Soucek in 2014 and continues to show clinical promise as the first direct inhibitor of MYC.
“Our first Omomyc-derived compound, OMO-103, successfully completed a phase I clinical trial in October 2022. Notably, this is the first MYC inhibitor to have ever reached this stage of clinical development. However, given that the in vivo stability of these therapeutic proteins can be affected by proteolytic degradation, the half-life duration of Omomyc had been questioned in the past,” explained Laura Soucek, co-Director of Preclinical and Translational Research at VHIO, Chief Executive Officer of Peptomyc, and an ICREA Research Professor.
The maintenance of the structural integrity of therapeutic proteins in the target tissue enables them to deliver their lasting anti-cancer blows. In this present study, Peptomyc investigators and researchers of VHIO’s Models of Cancer Therapies Group led by Laura Soucek performed pharmacokinetic analysis to assess the in vivo stability of Omomyc in blood serum and tumour tissue in a xenograft mouse model of colorectal cancer.
“Omomyc promises a new therapeutic avenue to target MYC, a most-wanted cancer-causing protein. Here, our findings provide evidence that Omomyc persists in tumour tissue longer than in blood,” said Soucek, co-corresponding author of this present study.
The initial preclinical studies on the purified Omomyc mini-protein evidenced its long terminal half-life in plasma (estimated to be >60 h in mice). Up until now, the proportion of tumour distribution and, most importantly, the structural integrity of the drug in tumour tissue have remained unknown.
“To date, only indirect approaches using either radioactively or fluorescently labelled Omomyc, have been used to address this question. The use of such covalent markers may however alter the intrinsic stability of the therapeutic protein of interest or could reflect the kinetic behaviour of only a portion of the functionally active molecule,” added Marie-Eve Beaulieu, co-founder and Chief Scientific Officer of Peptomyc, and co-corresponding author.
To more accurately calculate the absolute levels of this mini-protein’s structural integrity, the investigators used a label-free, high-resolution mass spectrometry approach for the first time and assessed the distribution of intact Omomyc to the tumour following intravenous administration in mice.
Results confirm that Omomyc not only reaches the tumour after 2 hours following intravenous administration at tissue concentrations within the range of serum but also that the tumour concentrations are higher than serum and persist there for at least 72 hours.
“Our findings are especially relevant now that Omomyc is being evaluated in clinical trials (2) since pharmacokinetic data are usually collected by analysis of blood samples in clinical practice,” added Soucek.
Reported results indicate for the first time that Omomyc behaves as a stable protein in tumour tissue and that the pharmacokinetics studies performed in blood (serum and plasma) samples, in preclinical models or in standard clinical practice, provide a likely underestimation of its distribution and persistence in the tumour compartment.
“Additionally, our described methodology, while not straightforward to implement in the normal routine of a clinical trial, could potentially be used for more accurately quantifying other therapeutic mini-proteins that might also display different stability in tumour tissue compared to blood samples,” concluded Laura Soucek, Principal Investigator of VHIO’s Models of Cancer Therapies Group.
