Long-Term Systemic Expression of a Novel PD-1 Blocking Nanobody from an AAV Vector Provides Antitumor Activity without Toxicity

Silva-Pilipich, Noelia; Martišová, Eva; Ballesteros-Briones, María Cristina; Hervás-Stubbs, Sandra; Casares, Noëlia; González‐Sapienza, Gualberto; Smerdou, Cristian; Vanrell, Lucía

doi:10.3390/biomedicines8120562

Cited by 15 publications

(11 citation statements)

References 56 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, a PD-1-specific scFv-Fc fusion protein was delivered by a Her2-targeted AAV vector, leading to reduced tumor growth in mouse models [111]. AAV vectors provide sustained nanobody expression both locally and systemically in preclinical models of human diseases, including solid tumors [112,113].…”

Section: Adeno-associated Viral Vectorsmentioning

confidence: 99%

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Blanco

Chocarro

Fernández-Rubio

et al. 2023

IJMS

View full text Add to dashboard Cite

Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.

show abstract

Section: Adeno-associated Viral Vectorsmentioning

confidence: 99%

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Blanco

Chocarro

Fernández-Rubio

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…To overcome these limitations, alternative strategies to produce mAbs in vivo have been widely investigated. Adeno-associated viruses (AAVs) have had a leading role in the development of gene therapy strategies aiming at the production of monoclonal antibodies for the treatment of several disorders, including cancer [35][36][37][38][39]. However, the sustained transgene expression achieved using this viral vector may not be adequate for the production of immunostimulatory monoclonal antibodies due to their often narrow therapeutic windows [40].…”

Section: Expression Of Immunostimulatory Antibody-based Moieties By Mrnamentioning

confidence: 99%

Advances in mRNA-based drug discovery in cancer immunotherapy

Trani

Fernandez‐Sendin

Cirella

et al. 2021

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

Introduction: Immune checkpoint inhibitors and adoptive T-cell therapy based on chimeric antigen receptors are the spearhead strategies to exploit the immune system to fight cancer.To take advantage of the full potential of the immune system, cancer immunotherapy must incorporate new biotechnologies such as mRNA technology that may synergize with already approved immunotherapies and act more effectively on immune targets. Areas covered: This review describes the basics of mRNA biotechnology and provides insight into the recent advances in the use of mRNA for the local and systemic delivery of immunostimulatory antibodies, proinflammatory cytokines or for optimizing adoptive Tcell therapy. Expert opinion: mRNA-based nanomedicines have great potential to expand the arsenal of immunotherapy tools due to their ability to simplify and accelerate drug development and their suitability for transient and local expression of immunostimulatory molecules, whose systemic and sustained expression would be toxic. The success of mRNA-based COVID-19 vaccines has highlighted the feasibility of this approach. Continuous advances in the delivery and construction of RNA-based vectors hold promise for improvements in clinical efficacy. Information Classification: General Article highlights• Immunotherapy is a breakthrough in cancer treatment, and mRNA-based drugs can provide novel strategies to harness the immune system to fight cancer.• mRNA technology has successfully been applied to the in vivo production of conventional or bispecific antibodies, as a strategy to reduce the toxicity associated with repeated and high doses of antibodies.• Cytokine-based immunotherapy encoded by mRNAs aims to raise the concentration of cytokine/s in the tumor microenvironment, while minimizing the systemic exposure and toxicity associated with the administration of the recombinant proteins.• Ex vivo transient engineering of T cells with mRNA molecules has been evaluated for adoptive cell transfer in pre-clinical and clinical studies. Impressively, advances in delivery technology have allowed in vivo targeting of the therapeutic RNAs to T lymphocytes.• Development of mRNA-based immunotherapies has to overcome current limitations of this technology, but further refinements will expand the cancer immunotherapy applications.

show abstract

“…In fact, this approach was used by us to deliver in vivo a novel anti-PD-1 nanobody (Nb11) capable of blocking the PD-1 / PD-L1 interaction for mouse and human molecules [ 78 ]. This study showed that sustained AAV-mediated expression of the Nb11 prevented colon adenocarcinoma tumor formation in 30% of mice, significantly increasing survival without evidence of toxicity or autoimmune events.…”

Section: Aav Vectors Expressing Nanobodies For Cancer Treatmentmentioning

confidence: 99%

A Small Virus to Deliver Small Antibodies: New Targeted Therapies Based on AAV Delivery of Nanobodies

2021

Self Cite

View full text Add to dashboard Cite

Nanobodies are camelid-derived single-domain antibodies that present some advantages versus conventional antibodies, such as a smaller size, and higher tissue penetrability, stability, and hydrophilicity. Although nanobodies can be delivered as proteins, in vivo expression from adeno-associated viral (AAV) vectors represents an attractive strategy. This is due to the fact that AAV vectors, that can provide long-term expression of recombinant genes, have shown an excellent safety profile, and can accommodate genes for one or several nanobodies. In fact, several studies showed that AAV vectors can provide sustained nanobody expression both locally or systemically in preclinical models of human diseases. Some of the pathologies addressed with this technology include cancer, neurological, cardiovascular, infectious, and genetic diseases. Depending on the indication, AAV-delivered nanobodies can be expressed extracellularly or inside cells. Intracellular nanobodies or “intrabodies” carry out their function by interacting with cell proteins involved in disease and have also been designed to help elucidate cellular mechanisms by interfering with normal cell processes. Finally, nanobodies can also be used to retarget AAV vectors, when tethered to viral capsid proteins. This review covers applications in which AAV vectors have been used to deliver nanobodies, with a focus on their therapeutic use.

show abstract

Long-Term Systemic Expression of a Novel PD-1 Blocking Nanobody from an AAV Vector Provides Antitumor Activity without Toxicity

Cited by 15 publications

References 56 publications

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Advances in mRNA-based drug discovery in cancer immunotherapy

A Small Virus to Deliver Small Antibodies: New Targeted Therapies Based on AAV Delivery of Nanobodies

Contact Info

Product

Resources

About