From a layman’s perspective, the assertion that Omomyc natively possessed cell penetrating capacity just seemed contradictory to the characterisation of Omomyc in Soucek’s previous articles, the Methods and Compositions for the Treatment of Cancer patent and Phylogica’s statements/findings in the February newsletter
Omomyc inhibitor of MYC… is not able to get inside cells by itself.
In contrast a control Omomyc protein, which lacked our Phylomer CPP and therefore couldn’t penetrate cells, had no effect.
Actually, the abstract on the new generation of Omoyc-based inhibitors to be presented at the American Association for Cancer Research Annual Meeting on April 20 raised two questions for me.
The following is taken from the abstract body
Omomyc has so far been utilized exclusively as a transgene and served as a successful proof of principle. Here we discuss our current research with Omomyc and our efforts to develop a clinically viable approach to Myc inhibition.
One is based on the direct use of Omomyc itself as a peptide since we have discovered that it natively possesses cell-penetrating activity and it rapidly biodistributes to the lung and brain after intranasal administration. We are finding that the Omomyc peptide - like its transgenic counterpart before - has a therapeutic impact and we are continuing with the preclinical validation of this innovative therapeutic approach to pharmacological Myc inhibition.
The second approach takes advantage of state-of-the-art nanocarrier technology to deliver Omomyc systemically, that can be combined with tumour-targeting ligands. These two novelMyc inhibition strategies have the potential to be translated rapidly to the clinic. (1)
The first question was - if Omomyc itself “natively possesses” cell-penetrating activity, does it still need a separate cell-penetrating peptide for intracellular access and efficacy?
The second was - is nanocarrier technology being proposed as an alternative approach to the intracellular delivery of Omomyc, negating the need for CPP delivery?
I note that the Methods and Compositions for the Treatment of Cancer patent abstract says
The invention relates to a Myc dominant negative mutant, called Omomyc, for use in medicine and for use in the prevention and/or treatment of cancer. The invention also refers to a fusion protein comprising Omomyc and pharmaceutical composition thereof and their use in medicine and, in particular, for treatment of cancer. (2)
Specific claim is made for a conjugate comprising Omomyc, or a functional variant thereof, and a chemical moiety that facilitates its cellular uptake, including where the chemical moiety that facilitates cellular uptake is a cell penetrating peptide and where Omomyc and the cell penetrating peptide form a fusion protein.
Further explanation is provided
In a preferred embodiment, said cell-penetrating peptide is not the endogenous Omomyc cell penetrating peptide. (2)
Thus, the patent suggests preference for achieving cellular uptake through use of a fusion protein comprising Omomyc and a separate cell penetrating peptide.
The patent also sheds some light on the proposed use of a nanocarrier in the potential cancer therapy (NB: it is not intended as an alternative/substitute to a CPP for intracellular delivery)
It will be understood that the formulation of Omomyc or of the functionally equivalent variant thereof in a nanoparticle is not intended or is not solely intended for facilitating the access of the Omomyc to the interior of the cell but to protect Omomyc from degradation and/or for facilitating targeting of the nanoparticle to the organ of interest…
Despite the fact that Omomyc and the conjugates and fusion proteins containing Omomyc are capable of translocating across biological membranes… it may also be convenient to formulate the conjugates or fusion proteins comprising Omomyc in nanoparticles. The nanoparticles may contribute to preserve the integrity of the polypeptide in the biological fluids until it reaches the target organ. Moreover, in the case of compositions comprising an antitumor agent, encapsulation of the composition may decrease secondary effects caused by the antitumor agent. Lastly, nanoparticles can also be modifiedso as to include moieties which allow the targeting of the nanoparticule to an organ of interest.(2)
Thus, the patent suggests that the intended role of a nanocarrier isn’t in intracellular delivery but rather for protection of the drug cargo against degradation, assistance in targeting the organ of interest and reduction of secondary effects caused by the antitumour drug.
Putting everything together, is the suggestion that the Omomyc-based cancer therapeutic could be an IV-administered Omomyc +CPP fusion protein combined with an established cancer drug (such as docetaxel), encapsulated within nanoparticles (which have tumour-binding ligands presenting on the surface)? (3) Or, alternativley, an intranasally delivered formulation for brain and lung cancer?
Finally, a couple of further points of interest about the patenting of Omomyc for the treatment of cancer
With respect to the WIPO patent mentioned above, the patent assignee is Vall d’Hebron Institute of Oncology. Laura Soucek and Marie-Eve Beaulieu are named as the inventors. Priority date is 7 May, 2013
A WIPO patent with priority date of 13 January 2012 claims use of Omomyc in the construct of a “Cancer-specific suicide gene for cell-based and gene therapy”. Patent assignee is the Sloan Kettering Institute for Cancer Research with note that the US government has certain rights in the invention. (4)
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