Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

Särkioja, Merja; Pesonen, Sari; Raki, Mari; Hakkarainen, Tanja; Salo, Jarmo A.; Ahonen, M.; Kanerva, Anna; Hemminki, Akseli

doi:10.1038/gt.2008.56

Cited by 38 publications

(45 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are in agreement with previous studies, suggesting that RGD or 5/3 modification of the Ad5 fiber knob can, at least partly, avoid neutralization from preexisting Ad5 NAbs. 42,43 Ad5fk FWKT (GFP), Ad5f35(GFP) and Ad5fk3(GFP) show a tendency to remain in the plasma fraction, which may be explained by decreased interaction with CAR and complement receptor 1 on human erythrocytes. 30 Beneficial effects of fiber modification could not have been observed in a standard neutralization assay with heat-inactivated plasma, which strongly support the use of the ex vivo blood loop system as a more accurate preclinical model.…”

Section: Oncolytic Adenovirus With Somatostatin Motifs J Leja Et Almentioning

confidence: 99%

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

Leja

Nilsson

et al. 2011

Gene Ther

Self Cite

View full text Add to dashboard Cite

We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackieadenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR 2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systemic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.

show abstract

Section: Oncolytic Adenovirus With Somatostatin Motifs J Leja Et Almentioning

confidence: 99%

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

Leja

Nilsson

et al. 2011

Gene Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…This modification enhances transduction, but does not result in complete escape from immune responses against the Ad5 capsid as only the fiber is modified. 10,11 Moreover, it is unknown if Ad5/3 is suitable for intravenous delivery which might have some advantages over the more typical intratumoral delivery. 12 In this regard, the use of adenovirus based fully on serotype 3 is appealing, 13 for example, because its primary receptor desmoglein 2 is highly expressed in advanced tumors.…”

Section: Introductionmentioning

confidence: 99%

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

et al. 2017

View full text Add to dashboard Cite

Vaccination with dendritic cells (DCs), the most potent professional antigen-presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumors induce immunosuppression in their microenvironment that suppresses and impairs the function of DCs. Therefore, human clinical trials with DC therapy have often been disappointing. To improve the therapeutic efficacy and to overcome the major obstacles of DC therapy, we generated a novel adenovirus, Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 and expresses hCD40L for induction of antitumor immune response. The specific aim is to enhance DCs function. Data from a human cancer patient indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, patient data suggested that virally produced hCD40L can activate DCs in situ. The virus was efficient in vitro and had potent antitumor activity in vivo. In a syngeneic model, tumors treated with Ad5/3-CMV-mCD40L virus plus DCs elicited greater antitumor effect as compared with either treatment alone. Moreover, virally coded CD40L induced activation of DCs, which in turn, lead to the induction of a Th1 immune response and increased tumorspecific T cells. In conclusion, Ad3-hTERT-CMV-hCD40L is promising for translation into human trials. In particular, this virus could enable successful dendritic cell therapy in cancer patients.

show abstract

“…Even if a suitably large self-protein was determined and could show hexon coverage, then modifications to the fiber may also be required to block neutralizing antibody sites on the fiber due to the extension away from the capsid of this protein. Two recent reports have indicated that fiber modifications may help Ad vectors escape the immune response [55,56], and therefore this would certainly be something that requires further investigation in combination with finding suitable alternate shielding molecules. …”

Section: Discussionmentioning

confidence: 99%

Assessment of Genetic Shielding for Adenovirus Vectors

Hedley

Krendelshchikov

Kim

et al. 2009

TOGTJ

View full text Add to dashboard Cite

Development of adenovirus (Ad) vectors in the clinical context has highlighted that vector efficacy may be limited by the host humoral response due to pre-existing titers of neutralizing antibodies against the vector itself in humans. Further, multiple dosing of Ad vectors based on serotype 5 would be limited. Current immune evasion strategies being investigated by other laboratories are only applicable to non-replicating vectors. Therefore we have proposed genetic shielding as an alternate that would be applicable to both non-replicating and conditionally replicating Ad vectors. Genetic shielding would encapsulate fusion of a self-protein to Ad minor capsid protein, pIX, as a means to cloak immunogenic capsid epitopes and prevent neutralization of Ad vectors through Ad specific antibodies. In the development of a suitably shielded Ad vector we choose several self-proteins that we attempted to fuse to pIX. We have also used an indirect method to conjugate albumin to the capsid through an albumin binding domain fused to pIX. Despite attaining novel pIX modified Ad vectors we found that none of the pIX attached molecules in this study prevented neutralizing antibodies from halting gene transfer.

show abstract

Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

Cited by 38 publications

References 35 publications

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

Assessment of Genetic Shielding for Adenovirus Vectors

Contact Info

Product

Resources

About