12 research outputs found
Aptamers against live targets: Is in vivo SELEX finally coming to the edge?
Targeted therapeutics underwent a revolution with the entry of monoclonal antibodies in the medical toolkit. Oligonucleotide aptamers form another family of target agents that have been lagging behind in reaching the clinical arena in spite of their potential clinical translation. Some of the reasons for this might be related to the challenge in identifying aptamers with optimal in vivo specificity, and the nature of their pharmacokinetics. Aptamers usually show exquisite specificity, but they are also molecules that display dynamic structures subject to changing environments. Temperature, ion atmosphere, pH, and other variables are factors that could determine the affinity and specificity of aptamers. Thus, it is important to tune the aptamer selection process to the conditions in which you want your final aptamer to function; ideally, for in vivo applications, aptamers should be selected in an in vivo-like system or, ultimately, in a whole in vivo organism. In this review we recapitulate the implementations in systematic evolution of ligands by exponential enrichment (SELEX) to obtain aptamers with the best in vivo activity
ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents
Aptamer-iRNAs as Therapeutics for Cancer Treatment
Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for the delivery of many different types of therapeutic cargos. Here we focus the review on interfering RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA, microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of cancer therapy
Decoy-based, targeted inhibition of STAT3: A new step forward for B cell lymphoma immunotherapy
Increasing evidence has linked the aggressiveness of non-Hodgkin’s lymphoma, in
particular activated B cell-like type diffuse
large B cell lymphomas (ABC-DLBCL), to
signaling by toll-like receptor 9 (TLR9)/
MyD88 and STAT3. In this issue of Molecular Therapy, Zhao et al.1 describe a dual function molecule comprising a clinically-relevant TLR9 agonist (CpG7909) fused to a
STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN).
CpG-STAT3dODN blocked STAT3 DNA
binding and activity, thus reducing expression of downstream target genes, such as
MYC and BCL2L1, in human and mouse
lymphoma cells. These effects led to the
generation of lymphoma cell-specific CD8/
CD4-dependent T cell immunity that could
protect mice from tumor rechallenge
Aptamer-iRNAs as Therapeutics for Cancer Treatment
Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment). This method has allowed the selection of aptamers to different types of molecules. Since then, many aptamers have been described for the potential treatment of several diseases including cancer. It has been described over the last few years that aptamers represent a very useful tool as therapeutics, especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for the delivery of many different types of therapeutic cargos. Here we focus the review on interfering RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA, microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of cancer therapy
In Silico Aptamer Docking Studies: From a Retrospective Validation to a Prospective Case Study'TIM3 Aptamers Binding
Complementing Systematic Evolution of Ligands by EXponential Enrichment (SELEX) technologies with in silico prediction of aptamer binders has attracted a lot of interest in the recent years. We propose a workflow involving 2D structure prediction, 3D RNA modeling using Rosetta and docking to the target protein with 3dRPC for: (i) prediction of the binding mode of our two previously reported potent (Kd < 50 nmol/l) murine TIM3 aptamers, and (ii) the prioritization of TIM3 aptamers that were enriched in the SELEX workflow. The procedure was first validated in five different study cases. As a novelty, cluster analysis of the docked poses was carried out and shown to be useful in reproducing the binding mode or at least in identifying the binding site and the experimental aptamer-protein interactions. For TIM3, our therapeutic target of interest, a plausible binding site and binding mode was identified that might explain the lack of cross-reactivity in murine over human TIM-3. Concerning the prioritization of the aptamers, the inclusion of the cluster analysis as an additional criterion following a rank-by-rank approach is discussed and compared with the performance of the docking scoring function alone for two validation cases and for the prospective assessment of the novel aptamers as TIM3 binders
Aptamer-iRNAs as therapeutics for cancer treatment
Aptamers are single-stranded oligonucleotides (ssDNA or ssRNA) that bind and recognize
their targets with high affinity and specificity due to their complex tertiary structure. Aptamers are
selected by a method called SELEX (Systematic Evolution of Ligands by EXponential enrichment).
This method has allowed the selection of aptamers to different types of molecules. Since then, many
aptamers have been described for the potential treatment of several diseases including cancer. It has
been described over the last few years that aptamers represent a very useful tool as therapeutics,
especially for cancer therapy. Aptamers, thanks to their intrinsic oligonucleotide nature, present
inherent advantages over other molecules, such as cell-based products. Owing to their higher tissue
penetrability, safer profile, and targeting capacity, aptamers are likely to become a novel platform for
the delivery of many different types of therapeutic cargos. Here we focus the review on interfering
RNAs (iRNAs) as aptamer-based targeting delivered agents. We have gathered the most reliable
information on aptamers as targeting and carrier agents for the specific delivery of siRNAs, shRNA,
microRNAs, and antisense oligonucleotides (ASOs) published in the last few years in the context of
cancer therapy
Aptamers against live targets: Is in vivo SELEX finally coming to the edge?
Targeted therapeutics underwent a revolution with the entry of monoclonal antibodies in the medical toolkit. Oligonucleotide aptamers form another family of target agents that have been lagging behind in reaching the clinical arena in spite of their potential clinical translation. Some of the reasons for this might be related to the challenge in identifying aptamers with optimal in vivo specificity, and the nature of their pharmacokinetics. Aptamers usually show exquisite specificity, but they are also molecules that display dynamic structures subject to changing environments. Temperature, ion atmosphere, pH, and other variables are factors that could determine the affinity and specificity of aptamers. Thus, it is important to tune the aptamer selection process to the conditions in which you want your final aptamer to function; ideally, for in vivo applications, aptamers should be selected in an in vivo-like system or, ultimately, in a whole in vivo organism. In this review we recapitulate the implementations in systematic evolution of ligands by exponential enrichment (SELEX) to obtain aptamers with the best in vivo activity
CD28 Aptamers as Powerful Immune Response Modulators
CD28 is one of the main costimulatory receptors responsible for the proper activation of T lymphocytes. We have isolated two aptamers that bind to the CD28 receptor. As a monomer, one of them interfered with the binding of CD28 to its ligand (B7), precluding the costimulatory signal, whereas the other one was inactive. However, dimerization of any of the anti-CD28 aptamers was sufficient to provide an artificial costimulatory signal. No antibody has featured a dual function (i.e., the ability to work as agonist and antagonist) to date. Two different agonistic structures were engineered for each anti-CD28 aptamer. One showed remarkably improved costimulatory properties, surpassing the agonistic effect of an anti-CD28 antibody. Moreover, we showed in vivo that the CD28 agonistic aptamer is capable of enhancing the cellular immune response against a lymphoma idiotype and of prolonging survival of mice which receive the aptamer together with an idiotype vaccine. The CD28 aptamers described in this work could be used to modulate the immune response either blocking the interaction with B7 or enhancing vaccine-induced immune responses in cancer immunotherapy
ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models. Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents