Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

Kramer, Katrin; Shields, Nicholas J.; Poppe, Viola; Young, Sarah L.; Walker, Greg F.

doi:10.1016/j.ymthe.2016.10.001

Cited by 28 publications

(46 citation statements)

References 42 publications

(56 reference statements)

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“…A pH titration experiment was performed to prove the pH responsiveness of the PC7A polyplex (Figure S3, Supporting Information). CpG activates TLR‐9 located at the inner surface of the endosomal membrane . Since free CpG, an oligodeoxynucleotide, has relatively low uptake in immune cells, CpG encapsulated in the nanoparticle can significantly enhance its bioavailability, and thus its efficiency, in boosting innate immunity .…”

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confidence: 99%

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

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Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically “cold” tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These “cold” tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of “cold” tumors, resulting in a more diversified antitumor T‐cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane‐coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T‐cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor‐specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off‐the‐shelf therapeutics.

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Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

et al. 2019

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“…26 The bis-aryl hydrazone bond was chosen for the conjugation of CpG to OVA, as it has been reported to be biologically stable. 2 , 26 − 28 The conjugation strategy is shown in Figure 1 , in which the terminal amine of the CpG was modified to an aromatic aldehyde by reacting it with the activated ester of the linker succinimidyl 4-formylbenzoate (4FB) and the unreacted linker was removed by spin filtration. The substitution of the CpG with the 4FB linker was 100% complete, as determined by reacting the 4FB-modified CpG with 2-hydrazinopyridine and measuring the formation of the bis-aryl hydrazone bond at 360 nm.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, these results suggest that even when conjugated through a stable linker to OVA, CpG can activate APCs, and the linking strategy does not restrict the activation of TLR9, as shown in previous studies. 2 , 6 , 7 , 34 The activation of APCs, such as BMDCs, with the expression of activation markers is necessary for a T-cell response. For T-cells to get activated and differentiated into effector cells, activated DCs process antigen and present it on MHC-I and MHC-II molecules at the same time as displaying co-stimulatory receptors.…”

Section: Resultsmentioning

confidence: 99%

“… 4 No difference in the BMDC activation between the 5′ and 3′ conjugates and the mixture of CpG and OVA may therefore be due to a similar upregulation of activation markers on BMDCs by CpG from a certain threshold concentration, as discussed previously. 2 …”

Section: Resultsmentioning

confidence: 99%

“… 12 − 14 Co-delivery of an antigen with CpG has been shown in vitro and in vivo to enhance antigen presentation to T-cells, the activation and differentiation of T-cells into T H 1 and cytotoxic T lymphocytes (CTL), and the cytotoxicity of effector T-cells compared with delivery as a mixture. 2 , 4 , 5 , 8 , 15 , 16 The enhanced immune response observed when co-delivering an antigen and CpG is believed to be due to their simultaneous internalization by an APC. When delivered as a mixture, only one of the two agents might be internalized, leading to either an activated APC that does not present the antigen to T-cells or an APC that may present the antigen, however, without being fully activated, thereby not being able to induce a full T-cell response.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Study of 5′- and 3′-Linked CpG–Antigen Conjugates for the Induction of Cellular Immune Responses

2017

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Conjugation of CpG to an antigen induces a stronger immune response compared to that of the mixture. This study compares the in vitro immunostimulatory activity of CpG conjugated via either its 5′ or 3′ end to the model antigen ovalbumin (OVA). CpG modified with an amine at either the 5′ or 3′ end was conjugated to OVA via a stable bis-aryl hydrazone bond. Similar levels of CpG conjugation to OVA were observed for both conjugates on the basis of the absorbance at 360 nm for the formation of the bis-aryl hydrazone bond, which determined 2.8 ± 0.3 CpGs linked per OVA. Both the 5′ and 3′ CpG–OVA conjugates had similar size-exclusion chromatography elution profiles. The immunostimulatory properties of the conjugates were determined by dendritic cells (DCs) and T-cells isolated from mice. The activation of DCs was determined by the upregulation of activation markers CD86 and CD40. T-cells were co-cultured with stimulated DCs, and the immunogenicity was determined by measuring T-cell proliferation and interferon γ production. Both the CpG 5′- and 3′-linked conjugates induced the same level (p > 0.5) of DC activation markers, which were significantly higher than those of the untreated control. Similarly, T-cell assays showed no significant difference (p > 0.5) between the 5′ and 3′ conjugates with respect to T-cell proliferation and interferon γ production. The 5′ and 3′ conjugates induced T-cell activation significantly higher than the mixture of CpG and OVA. This study showed that the end at which CpG is conjugated to an antigen has no influence on the generation of a T-cell-based immune response in vitro.

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Nucleic Acids as Adjuvants

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Oligonucleotide‐Based Drugs and Therapeutics

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Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

Cited by 28 publications

References 42 publications

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

Comparative Study of 5′- and 3′-Linked CpG–Antigen Conjugates for the Induction of Cellular Immune Responses

Nucleic Acids as Adjuvants

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