BackgroundDespite substantial progress observed in the field of targeted therapies for cancer, there is still a major unmet clinical need for truly personalized medicine approaches. Aummune’s innovative proprietary technology enables a personalized anti-cancer treatment based on a process of selecting and identifying specific functional aptamers – structured single-stranded DNA (ssDNA) oligonucleotides, that are able to bind a large variety of targets with high affinity and specificity.MethodsThe Bispecific Personalized Aptamer is comprised of two ssDNA oligonucleotides arms joined together by a dimerization site. One arm of the Bispecific Personalized Aptamer is the outcome of Aummune’s innovative platform,1 identifying functional aptamer sequences with the ability to kill tumor target cells, while leaving healthy tissue intact. The second arm is a constant aptamer sequence that binds to cytotoxic T lymphocytes. The two aptamer arms of the bispecific structure are bridged together by complementary sequences that form a CpG- rich domain designed to induce TLR9-mediated Antigen Presenting Cells (APCs) stimulation.ResultsWe have demonstrated a successful identification of a personalized aptamer arm using HCT116 colon carcinoma cells as a target. When hybridized to the constant, T cell engager arm, the bispecific entity has demonstrated potent yet selective tumor cell death induction. The Bispecific Aptamer has been further shown to significantly attenuate HCT116 tumor growth in vivo, an effect that was translated into a benefit to survival of treated mice.ConclusionsWe have provided a proof-of-concept for Aummune’s platform ability to identify an effective functional personalized aptamer, which did not harm healthy cells. The Bispecific Aptamer’s exerted function in vitro has translated into a significant effect in vivo. Based on the personal approach and multiplicity of modes of action, the Bispecific Personalized Aptamer could have an effect in a broad spectrum of cancer indications.ReferenceMamet N, et al. Commun Biol. 2020
BackgroundT-cell engagers are bispecific molecules directed against the CD3 complex on one end and a tumor specific antigen on the other end, allowing a physical link of T cell to a tumor cell, resulting in tumor killing and immune activation. Bispecific molecules harnessing and redirecting T-cells towards tumor cells are a promising therapeutic agents. Aptamers are single stranded oligonucleotides with binding and recognition propensities similar to those of antibodies. Aptamers have a number of advantages over bispecific antibodies including shorter generation time and low immunogenicity. Thus, aptamers capable of targeting T cells would have great potential for use as anti-cancer therapeuticsMethodsSystematic evolution of ligands by exponential enrichment (SELEX) methodology was employed in order to identify a novel CD3e binding aptamer. CD3 binding aptamer was subsequently linked into a bispecific T cell engager structure with a tumor-targeting aptameric arm. The tumor-targeting aptamer is developed by Aummune's proprietary tailored therapeutic platform.1 based on identifying functional aptamer sequences capable of specifically killing targeted tumor cells and sparing healthy tissue .Exemplary bispecific aptamers were tested for T cell stimulation by flow cytometry. In vivo antitumor activity was investigated in syngeneic and in xenograft tumor models.ResultsWe have successfully identified a novel CD3e –targeting aptamer with a Kd of 31nM. A bispecific T cell engager comprised of this aptamer and a tumor-targeting aptamer induced a potent stimulation of T cells in vitro, resulting in CD69 upregulation and IFNg secretion.Next, the CD3e targeting aptamer was hybridized to tumoricidal aptamers identified by Aummune's platform (VS12) to target either the human colon carcinoma HCT116 cells or (VS32) the murine triple negative breast cancer 4T1 cells. Both bispecific entities (CS6-VS12 and CS6-VS32) effectively lead to inhibition of tumor growth in vivo and increased survival in the corresponding models.ConclusionsOur data above provide a proof-of-concept for Aummune's Bispecific Aptamer efficacy and provide a framework for the clinical development of this novel tailored immune therapeutic agents. Indeed, we are currently in the process of developing a first-in-human clinical study in subjects with solid tumors.ReferenceMamet N, et al, Commun Biol 2020.
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