Journal articles: 'Targeted antigen delivery'

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Wengerter, Brian C., Joseph A. Katakowski, Jacob M. Rosenberg, Chae Gyu Park, Steven C. Almo, Deborah Palliser, and Matthew Levy. "Aptamer-targeted Antigen Delivery." Molecular Therapy 22, no. 7 (July 2014): 1375–87. http://dx.doi.org/10.1038/mt.2014.51.

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Bourque, Jessica, and Daniel Hawiger. "Applications of Antibody-Based Antigen Delivery Targeted to Dendritic Cells In Vivo." Antibodies 11, no. 1 (January 25, 2022): 8. http://dx.doi.org/10.3390/antib11010008.

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Recombinant immunoglobulins, derived from monoclonal antibodies recognizing the defined surface epitopes expressed on dendritic cells, have been employed for the past two decades to deliver antigens to dendritic cells in vivo, serving as critical tools for the investigation of the corresponding T cell responses. These approaches originated with the development of the recombinant chimeric antibody against a multilectin receptor, DEC-205, which is present on subsets of murine and human conventional dendritic cells. Following the widespread application of antigen targeting through DEC-205, similar approaches then utilized other epitopes as entry points for antigens delivered by specific antibodies to multiple types of dendritic cells. Overall, these antigen-delivery methodologies helped to reveal the mechanisms underlying tolerogenic and immunogenic T cell responses orchestrated by dendritic cells. Here, we discuss the relevant experimental strategies as well as their future perspectives, including their translational relevance.

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Kawasaki, Norihito, Weihsu Chen, Jose Vela, Corwin Nycholat, Igor Maricic, Kumar Vipin, Paul Crocker, Mitchell Kronenberg, and James Paulson. "Efficient lipid antigen presentation to NKT cells by targeting CD169/Siglec-1 on macrophages with its glycan ligand. (100.49)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 100.49. http://dx.doi.org/10.4049/jimmunol.186.supp.100.49.

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Abstract Natural killer T (NKT) cells are a subset of T cells expressing an invariant TCR with cross-species conserved specificity to glycolipid antigens in the CD1d restricted presentation. Recent studies have identified CD169/Siglec-1+ macrophages as antigen presenting cells for NKT cells. Here we show that delivery of the lipid antigen through CD169 on macrophages induces NKT cell activation. We developed CD169-targeted liposomes decorated with a specific glycan ligand of CD169 (9-N-biphenylcarboxyl-NeuAcα2-3Galβ1-4GlcNAc) and observed that CD169-targeted liposomes were captured by macrophages in the CD169-dependent manner, and delivered to lysosomes, the known site of lipid antigen loading on CD1d. We next investigated the ability of the CD169-targeted liposomes to promote NKT cell activation by delivery of a lipid antigen α-GalCer to macrophages. We found that macrophages pulsed with α-GalCer containing CD169-targeted liposomes efficiently presented the lipid antigen to NKT cells when transferred into the C57BL/6J mouse. Alternatively, intravenous injection of the α-GalCer containing CD169-targeted liposomes activated NKT cells 100-fold more efficiently than lipid antigen alone in vivo. CD169-targeted liposomes without α-GalCer did not activate NKT cells, demonstrating this activation is through cognate antigen recognition by NKT cells. These data demonstrate that CD169-targeted liposomes dramatically enhance lipid antigen delivery to macrophages for NKT cell activation in vivo.

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Wi, Tae In, Yeongseon Byeon, Ji Eun Won, Jae Myeong Lee, Tae Heung Kang, Jeong-Won Lee, Young Joo Lee, Anil K. Sood, Hee Dong Han, and Yeong-Min Park. "Selective Tumor-Specific Antigen Delivery to Dendritic Cells Using Mannose-Labeled Poly(d, l-lactide-co-glycolide) Nanoparticles for Cancer Immunotherapy." Journal of Biomedical Nanotechnology 16, no. 2 (February 1, 2020): 201–11. http://dx.doi.org/10.1166/jbn.2020.2883.

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A key issue in dendritic cell (DC)-based cancer immunotherapy is the effective delivery of tumor-specific antigens to DCs. To deliver antigens, non-viral vaccine system has been used in ex vivo manipulation. However, ex vivo manipulation is time-consuming, lacks quality control of DCs, and demonstrates low antigen delivery efficiency, which implicates that there are serious problems in therapeutic DC preparations. Therefore, we developed mannose (MN)-labeled poly(d, l-lactide-co-glycolide) (PLGA) nanoparticles (MN-PLGA-NPs) encapsulating tumor-specific antigens for targeted delivery to mannose receptors (MN-R) on DC surfaces without ex vivo manipulation. The MN-PLGA-NPs showed DC-selective delivery in tumor-bearing mice, leading to highly mature and activated DCs, which migrated to lymphoid organs, resulting in activation of cytotoxic CD8+ T cells. Additionally, MN-PLGA-NPs showed significant therapeutic efficacy in EG7 lymphoma tumorbearing mice. Our nano-platform technology can be used as a vaccine system to bypass ex vivo manipulation and enhance targeted delivery of tumor-specific antigens to DCs, which is well-suited for cancer immunotherapy.

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Swanson, Anna, Danli Wu, Isere Kuiatse, Hong-Sung Kim, Helen Heslop, Malcolm Brenner, and Patricia Yotnda. "Delivery of tumor-targeted immunotoxin by tumor-specific T cells (155.19)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 155.19. http://dx.doi.org/10.4049/jimmunol.186.supp.155.19.

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Abstract Immunotherapy of cancer using monoclonal antibodies and adoptive transfer of lymphocytes is showing considerable promise. Based on experience with other cancer therapeutics immunotherapeutic modalities, targeting discrete molecular components of the tumor, will prove superior to a single effector system. “Multitargeting” approaches will not only prevent tumor immune escape, they will also allow safer and potent anticancer therapies. We have engineered antigen specific T cells so that they can target tumor cells directly, and then release a potent toxin linked to a monoclonal antibody molecule thereby targeting an independent tumor antigen to the tumor reactive T cell. These engineered T cells were tested in vitro and in vivo in a xenograft model of B-lymphoma. We found that tumor antigen specific T cells retain their anti-tumor activity and tumor homing abilities even when transduced with a gene encoding a chimeric monoclonal antibody-toxin. The release of the targeted immunotoxin molecule occurs only after the T cell has engaged its tumor target. The combination of these two distinct effector systems (T cells and immunotoxin) targeting two distinct tumor antigens have superior anti-tumor activity than a single system targeting a single antigen, with no greater toxicity. By combining two highly specific and partially effective strategies for tumor destruction, we achieved selective and more effective tumor killing.

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Yuba, Eiji, Yoshiki Fukaya, Shin Yanagihara, Nozomi Kasho, and Atsushi Harada. "Development of Mannose-Modified Carboxylated Curdlan-Coated Liposomes for Antigen Presenting Cell Targeted Antigen Delivery." Pharmaceutics 12, no. 8 (August 11, 2020): 754. http://dx.doi.org/10.3390/pharmaceutics12080754.

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Specific delivery to antigen presenting cells (APC) and precise control of the intracellular fate of antigens are crucial to induce cellular immunity that directly and specifically attacks cancer cells. We previously achieved cytoplasmic delivery of antigen and activation of APC using carboxylated curdlan-modified liposomes, which led to the induction of cellular immunity in vivo. APCs express mannose receptors on their surface to recognize pathogen specifically and promote cross-presentation of antigen. In this study, mannose-residue was additionally introduced to carboxylated curdlan as a targeting moiety to APC for further improvement of polysaccharide-based antigen carriers. Mannose-modified curdlan derivatives were synthesized by the condensation between amino group-introduced mannose and carboxy group in pH-sensitive curdlan. Mannose residue-introduced carboxylated curdlan-modified liposomes showed higher pH-sensitivity than that of liposomes modified with conventional carboxylated curdlan. The introduction of mannose-residue to the liposomes induced aggregation in the presence of Concanavalin A, indicating that mannose residues were presented onto liposome surface. Mannose residue-introduced carboxylated curdlan-modified liposomes exhibited high and selective cellular association to APC. Furthermore, mannose residue-introduced carboxylated curdlan-modified liposomes promoted cross-presentation of antigen and induced strong antitumor effects on tumor-bearing mice. Therefore, these liposomes are promising as APC-specific antigen delivery systems for the induction of antigen-specific cellular immunity.

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Murty, Rohan, Abishek Sankaranarayanan, Isabella I. Bowland, Juan Mena-Lapaix, and Mark R. Prausnitz. "Angled Insertion of Microneedles for Targeted Antigen Delivery to the Epidermis." Pharmaceutics 14, no. 2 (February 1, 2022): 347. http://dx.doi.org/10.3390/pharmaceutics14020347.

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Peanut and tree nut allergies account for most food-induced anaphylactic events. The standard allergy immunotherapy approach involves subcutaneous injection, which is challenging because severe adverse reactions can occur when antigens spread systemically. Allergen localization within the epidermis (i.e., the upper 20–100 µm of skin) should significantly reduce systemic uptake, because the epidermis is avascular. Microneedle (MN) patches provide a convenient method for drug delivery to the skin, but they generally target both epidermis and dermis, leading to systemic delivery. In this study, we adapted MN technology for epidermal localization by performing angled insertion of 250 µm–long MNs that limits MN insertion depth mostly to the epidermis. We designed a biplanar insertion device to aid the repeatability of angled insertions into porcine skin ex vivo at specified angles (90°, 45°, and 20°). When compared to 90° insertions, MN application at 20° decreased mean insertion depth from 265 ± 45 µm to 97 ± 15 µm. Image analysis of histological skin sections revealed that acute-angle insertion increased epidermal localization of delivery for antigen-coated MNs from 25% ± 13% to 70% ± 21%. We conclude that angled insertion of MNs can target antigen delivery to epidermis.

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Shaw, Christine A., and Michael N. Starnbach. "Stimulation of CD8+ T Cells following Diphtheria Toxin-Mediated Antigen Delivery into Dendritic Cells." Infection and Immunity 74, no. 2 (February 2006): 1001–8. http://dx.doi.org/10.1128/iai.74.2.1001-1008.2006.

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ABSTRACT Recognition and clearance of many intracellular pathogens requires the activation and subsequent effector functions of CD8+ T lymphocytes. To stimulate CD8+ T cells by immunization, the target antigens must be delivered into the cytosol of host cells. There they can be processed into peptides and presented in the context of major histocompatibility complex class I molecules to antigen-specific CD8+ T cells. One method of delivering antigens into the cytosol is to fuse them to modified bacterial toxins that are able to enter mammalian cells. The expression pattern of the toxin receptors in the host will determine the cell population that the toxin fusion protein targets and will thus restrict antigen-specific T-cell recognition to the same population. In this study we describe the development and characterization of a diphtheria toxin (DT)-based antigen delivery system. Using CD11c-DTR transgenic mice that express the DT receptor in dendritic cells (DC), this system allows for targeted delivery of CD8+ T-cell antigen to DC. We show that antigen-specific CD8+ T cells proliferate in CD11c-DTR mice following immunization with catalytically inactive DT-antigen fusion proteins. We also show that a toxin-based system that restricts antigen delivery to DC results in more robust antigen-specific CD8+ T-cell proliferation than a toxin-based system that does not restrict delivery to a particular cell type. These results have implications for vaccine design, and they suggest that use of a toxin-based vector to target antigen to DC may be an effective way to induce a CD8+ T-cell response.

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Ciccotelli, Jo Erika, Helene Toussaint, Geza Erdos, Cara Carey, Simon Watkins, and Louis Falo. "Intradermal immunization with polyguanine conjugated antigens enables targeted and sustained delivery of protein antigens to dendritic cells in vivo. (APP3P.111)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 111.12. http://dx.doi.org/10.4049/jimmunol.192.supp.111.12.

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Abstract Effective vaccine design depends on the ability to target specific antigens to antigen presenting cells (APCs), including dendritic cells (DCs). Conjugation of proteins antigens to polyguanine (Poly(dG)) molecules is a novel immunization approach capable of transforming soluble antigens into aggregated particulates with exposed scavenger receptor (SR) ligands. We have previously shown that Poly(dG) conjugation to protein antigen results in increased antigen-specific helper and cytotoxic T cell responses, memory T cell induction, and antibody titers. Here, we specifically investigate mechanisms of Poly(dG)-conjugated antigen delivery and internalization. Compared to soluble OVA, Poly(dG)-OVA is rapidly and more efficiently internalized by bone marrow derived DCs in vitro, and this internalization is inhibited by scavenger receptor blockade. Importantly, in a mouse model intradermally injected Poly(dG)-OVA results in antigen persistence in the skin for up to 7 days. This is accompanied by increased antigen uptake by skin resident DCs and persistent migration of antigen loaded DCs to the draining lymph nodes. DCs exposed to Poly(dG)-OVA had increased expression of CCR7 and secretion of MCP-1, TNF-α, and IL-6. These results suggest that coupling Poly(dG) to protein antigens enables efficient DC targeting through SRs, prolonged delivery of antigens in vivo, and activation of innate immunity. This approach may be used to design more efficient antiviral and antitumor vaccines.

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Raiber, Eun-Ang, Calogero Tulone, Yanjing Zhang, Luisa Martinez-Pomares, Emily Steed, Anna M. Sponaas, Jean Langhorne, Mahdad Noursadeghi, Benjamin M. Chain, and Alethea B. Tabor. "Targeted Delivery of Antigen Processing Inhibitors to Antigen Presenting Cells via Mannose Receptors." ACS Chemical Biology 5, no. 5 (April 27, 2010): 461–76. http://dx.doi.org/10.1021/cb100008p.

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KNOX, D. P. "Development of vaccines against gastrointestinal nematodes." Parasitology 120, no. 7 (May 2000): 43–61. http://dx.doi.org/10.1017/s0031182099005764.

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Vaccination against complex metazoan parasites has become a reality with the development and registration of recombinant protein-based vaccines against the cattle tick Boophilus microplus and the sheep cestode Taenia ovis. Progress towards the development of similar vaccines against gastrointestinal nematodes, primarily of ruminants, is outlined within a framework of defining the practical requirements for successful vaccination, antigen selection, recombinant protein production and antigen delivery, be it mucosal delivery or DNA vaccination. Antigen selection strategies include the fractionation of complex, but protective, parasite extracts, the use of antibody probes, evaluation of excretory-secretory components and gut-expressed hidden antigens as well as antigens targeted on the basis of function such as enzyme activity. The difficulties being encountered in recombinant protein production and their solution are discussed as are the requirements for successful antigen delivery. Recent technological developments such as the use of functional genomics to identify new vaccine candidates and DNA vaccination to present the selected antigen to the host immune system are discussed and are anticipated to have a profound effect on vaccine development in the future.

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Woodham, Andrew W., Ross W. Cheloha, Jingjing Ling, Mohammad Rashidian, Stephen C. Kolifrath, Maia Mesyngier, Joao N. Duarte, et al. "Targeted delivery of antigens to CD11b+ cells via nanobodies induces strong antigen-specific T cell and anti-tumor responses." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 181.6. http://dx.doi.org/10.4049/jimmunol.200.supp.181.6.

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Abstract The variable regions of camelid heavy chain-only antibodies (nanobodies or VHHs) are the smallest antibody fragments that retain full antigen binding. Owing to their small size, ease of expression, and high tissue penetration, VHHs that recognize cell surface proteins on antigen-presenting cells (APCs) can serve as targeted delivery vehicles for antigens conjugated to them. We site-specifically attached antigens to the C-terminus of an anti-CD11b VHH (VHHCD11b), and then investigated the ability of the VHH-antigen conjugates to elicit antigen-specific T cell and anti-tumor responses in a mouse model of human papillomavirus (HPV)-induced cancer. This VHH had high affinity for CD11b+ dendritic cells (apparent KD = 204 ± 90 pM), and enhanced cross-presentation of a conjugated antigen (OVA257–264) in vitro. Mice immunized with the VHH conjugated to an immunodominant HPV16 E7 epitope (E749–57) had more E7-specific cytotoxic T cells compared to mice immunized with E7 peptide alone, conferring protection against HPV16 E7+ tumor cell challenge. Therapeutically, VHHCD11b-E7 vaccination resulted in greater numbers of CD8+ tumor infiltrating lymphocytes compared to mice receiving E7 peptide alone in HPV16+ tumor-bearing mice, as measured by in vivo non-invasive VHH-based positron emission tomography (PET), which correlated with tumor regression and increased survival. Thus, targeting CD11b for the delivery of antigens via VHHs may be a promising cancer immunotherapeutic strategy.

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Huston, James S., Mei-Sheng Tai, John McCartney, Peter Keck, and Hermann Oppermann. "Antigen recognition and targeted delivery by the single-chain Fv." Cell Biophysics 22, no. 1-3 (January 1993): 189–224. http://dx.doi.org/10.1007/bf03033874.

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Wang, Max Mu, Mi Ran Choi, Bin Zhang, and Nathan Gianneschi. "A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2564. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2564.

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2564 Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.

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Wang, Max Mu, Mi Ran Choi, Bin Zhang, and Nathan Gianneschi. "A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2564. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2564.

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2564 Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.

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kheirollahpour, Mehdi, Mohsen Mehrabi, Naser Mohammadpour Dounighi, Mohsen Mohammadi, and Alireza Masoudi. "Nanoparticles and Vaccine Development." Pharmaceutical Nanotechnology 8, no. 1 (February 6, 2020): 6–21. http://dx.doi.org/10.2174/2211738507666191024162042.

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In spite of the progress of conventional vaccines, improvements are required due to concerns about the low immunogenicity of the toxicity, instability, and the need for multiple administrations of the vaccines. To overcome the mentioned problems, nanotechnology has recently been incorporated into vaccine development. Nanotechnology increasingly plays an important role in vaccine development nanocarrier-based delivery systems that offer an opportunity to increase the cellular and humoral immune responses. The use of nanoparticles in vaccine formulations allows not only enhanced immunogenicity and stability of antigen, but also targeted delivery and slow release. Over the past decade, nanoscale size materials such as virus-like particles, liposomes, ISCOMs, polymeric, inorganic nanoparticles and emulsions have gained attention as potential delivery vehicles for vaccine antigens, which can both stabilize vaccine antigens and act as adjuvants. This advantage is attributable to the nanoscale particle size, which facilitates uptake by Antigen- Presenting Cells (APCs), then leading to efficient antigen recognition and presentation. Modifying the surfaces of nanoparticles with different targeting moieties permits the delivery of antigens to specific receptors on the cell surface, thereby stimulating selective and specific immune responses. This review provides an overview of recent advances in nanovaccinology.

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Dahlgren, David, and Hans Lennernäs. "Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective." Molecules 25, no. 12 (June 21, 2020): 2861. http://dx.doi.org/10.3390/molecules25122861.

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Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

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Campbell, Katrin, Vivienne L. Young, Braeden C. Donaldson, Matthew J. Woodall, Nicholas J. Shields, Greg F. Walker, Vernon K. Ward, and Sarah L. Young. "Delivering Two Tumour Antigens Survivin and Mucin-1 on Virus-Like Particles Enhances Anti-Tumour Immune Responses." Vaccines 9, no. 5 (May 6, 2021): 463. http://dx.doi.org/10.3390/vaccines9050463.

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Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future.

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Nabi, I. R., A. Le Bivic, D. Fambrough, and E. Rodriguez-Boulan. "An endogenous MDCK lysosomal membrane glycoprotein is targeted basolaterally before delivery to lysosomes." Journal of Cell Biology 115, no. 6 (December 15, 1991): 1573–84. http://dx.doi.org/10.1083/jcb.115.6.1573.

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Using surface immunoprecipitation at 37 degrees C to "catch" the transient apical or basolateral appearance of an endogenous MDCK lysosomal membrane glycoprotein, the AC17 antigen, we demonstrate that the bulk of newly synthesized AC17 antigen is polarly targeted from the Golgi apparatus to the basolateral plasma membrane or early endosomes and is then transported to lysosomes via the endocytic pathway. The AC17 antigen exhibits very similar properties to members of the family of lysosomal-associated membrane glycoproteins (LAMPs). Parallel studies of an avian LAMP, LEP100, transfected into MDCK cells revealed colocalization of the two proteins to lysosomes, identical biosynthetic and degradation rates, and similar low levels of steady-state expression on both the apical (0.8%) and basolateral (2.1%) membranes. After treatment of the cells with chloroquine, newly synthesized AC17 antigen, while still initially targeted basolaterally, appears stably in both the apical and basolateral domains, consistent with the depletion of the AC17 antigen from lysosomes and its recycling in a nonpolar fashion to the cell surface.

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Toussaint, Helene, Geza Erdos, and Louis D. Falo, Jr. "Targeted delivery of Poly(dG) conjugated protein antigens to antigen presenting cells results in efficient cross-priming in vivo (78.32)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 78.32. http://dx.doi.org/10.4049/jimmunol.182.supp.78.32.

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Abstract The development of strategies to efficiently and specifically deliver antigen to antigen presenting cells (APCs) in vivo is a major goal of vaccine design. Internalization of antigen by APCs is a crucial step in immune activation and the mechanism of antigen internalization and trafficking can influence localization in antigen processing compartments and the presentation of antigen to CD4+ or CD8+ T cells. We have designed an APC targeting strategy based on simple and direct coupling of Poly(dG) oligo deoxynucleotides to protein antigens. In comparison to soluble OVA, we find that conjugates of Poly(dG) and OVA (OVA-Poly(dG)) are rapidly internalized by DCs and transverse distinct intracellular processing pathways. OVA-Poly(dG) is both presented to OVA-specific CD4+ T cells (OT-II cells) and efficiently cross-presented to OVA-specific CD8+ T cells (OT-I cells) by DCs in vitro. Importantly, immunization of naïve animals by direct injection of OVA-Poly(dG) results in efficient priming of potent antigen specific CTL responses. Our results suggest that Poly(dG) can target antigen to APCs and serve as a potent adjuvant to induce strong CD8+ T cell-mediated immunity against tumors or viruses. Funding provided by NIH.

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Affandi, Alsya J., Joanna Grabowska, Katarzyna Olesek, Miguel Lopez Venegas, Arnaud Barbaria, Ernesto Rodríguez, Patrick P. G. Mulder, et al. "Selective tumor antigen vaccine delivery to human CD169+antigen-presenting cells using ganglioside-liposomes." Proceedings of the National Academy of Sciences 117, no. 44 (October 16, 2020): 27528–39. http://dx.doi.org/10.1073/pnas.2006186117.

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Priming of CD8+T cells by dendritic cells (DCs) is crucial for the generation of effective antitumor immune responses. Here, we describe a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1+antigen-presenting cells using gangliosides as targeting ligands. Ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro-generated monocyte-derived DCs (moDCs) and macrophages and by ex vivo-isolated splenic macrophages in a CD169-dependent manner. In blood, high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14+CD169+monocytes and Axl+CD169+DCs. Liposomal codelivery of tumor antigen and Toll-like receptor ligand to CD169+moDCs and Axl+CD169+DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8+T cells. Finally, Axl+CD169+DCs were present in cancer patients and efficiently captured ganglioside-liposomes. Our findings demonstrate a nanovaccine platform targeting CD169+DCs to drive antitumor T cell responses.

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Le Gall, Camille, Anna Cammarata, Lukas de Haas, Iván Ramos-Tomillero, Jorge Cuenca-Escalona, Kayleigh Schouren, Zacharias Wijfjes, et al. "Efficient targeting of NY-ESO-1 tumor antigen to human cDC1s by lymphotactin results in cross-presentation and antigen-specific T cell expansion." Journal for ImmunoTherapy of Cancer 10, no. 4 (April 2022): e004309. http://dx.doi.org/10.1136/jitc-2021-004309.

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BackgroundType 1 conventional dendritic cells (cDC1s) are characterized by their ability to induce potent CD8+ T cell responses. In efforts to generate novel vaccination strategies, notably against cancer, human cDC1s emerge as an ideal target to deliver antigens. cDC1s uniquely express XCR1, a seven transmembrane G protein-coupled receptor. Due to its restricted expression and endocytic nature, XCR1 represents an attractive receptor to mediate antigen-delivery to human cDC1s.MethodsTo explore tumor antigen delivery to human cDC1s, we used an engineered version of XCR1-binding lymphotactin (XCL1), XCL1(CC3). Site-specific sortase-mediated transpeptidation was performed to conjugate XCL1(CC3) to an analog of the HLA-A*02:01 epitope of the cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1). While poor epitope solubility prevented isolation of stable XCL1-antigen conjugates, incorporation of a single polyethylene glycol (PEG) chain upstream of the epitope-containing peptide enabled generation of soluble XCL1(CC3)-antigen fusion constructs. Binding and chemotactic characteristics of the XCL1-antigen conjugate, as well as its ability to induce antigen-specific CD8+ T cell activation by cDC1s, was assessed.ResultsPEGylated XCL1(CC3)-antigen conjugates retained binding to XCR1, and induced cDC1 chemoattraction in vitro. The model epitope was efficiently cross-presented by human cDC1s to activate NY-ESO-1-specific CD8+ T cells. Importantly, vaccine activity was increased by targeting XCR1 at the surface of cDC1s.ConclusionOur results present a novel strategy for the generation of targeted vaccines fused to insoluble antigens. Moreover, our data emphasize the potential of targeting XCR1 at the surface of primary human cDC1s to induce potent CD8+ T cell responses.

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Shrestha, Angita, Jean-Remy Sadeyen, and Munir Iqbal. "Enhancing Protective Efficacy of Poultry Vaccines through Targeted Delivery of Antigens to Antigen-Presenting Cells." Vaccines 6, no. 4 (November 15, 2018): 75. http://dx.doi.org/10.3390/vaccines6040075.

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Avian viral diseases including avian influenza, Marek’s disease and Newcastle disease are detrimental to economies around the world that depend on the poultry trade. A significant zoonotic threat is also posed by avian influenza viruses. Vaccination is an important and widely used method for controlling these poultry diseases. However, the current vaccines do not provide full protection or sterile immunity. Hence, there is a need to develop improved vaccines. The major aim of developing improved vaccines is to induce strong and specific humoral and cellular immunity in vaccinated animals. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to antigen-presenting cells (APCs) including dendritic cells, macrophages and B cells. APCs have a central role in the initiation and maintenance of immune responses through their ability to capture, process and present antigens to T and B cells. Vaccine technology that selectively targets APCs has been achieved by coupling antigens to monoclonal antibodies or ligands that are targeted by APCs. The aim of this review is to discuss existing strategies of selective delivery of antigens to APCs for effective vaccine development in poultry.

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Petzold, Cathleen, Sonja Schallenberg, Joel N. H. Stern, and Karsten Kretschmer. "Targeted Antigen Delivery to DEC-205+Dendritic Cells for Tolerogenic Vaccination." Review of Diabetic Studies 9, no. 4 (2012): 305–18. http://dx.doi.org/10.1900/rds.2012.9.305.

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AL Fayez, Nojoud, Elham Rouhollahi, Chun Yat Ong, Jiamin Wu, Anne Nguyen, Roland Böttger, Pieter R. Cullis, Dominik Witzigmann, and Shyh-Dar Li. "Hepatocyte-targeted delivery of imiquimod reduces hepatitis B virus surface antigen." Journal of Controlled Release 350 (October 2022): 630–41. http://dx.doi.org/10.1016/j.jconrel.2022.08.058.

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Muraoka, Daisuke, Naohiro Seo, Tae Hayashi, Yoshiro Tahara, Keisuke Fujii, Isao Tawara, Yoshihiro Miyahara, et al. "Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance." Journal of Clinical Investigation 129, no. 3 (February 11, 2019): 1278–94. http://dx.doi.org/10.1172/jci97642.

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Kouno, Michiyoshi, Norman Schechter, and John R. Stanley. "OI0245 Oral cancer treatment by tumor antigen–targeted drug delivery system." Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 117, no. 5 (May 2014): e338-e339. http://dx.doi.org/10.1016/j.oooo.2014.01.042.

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Chattergoon, Michael A., J. Joseph Kim, Joo-Sung Yang, Tara M. Robinson, Daniel J. Lee, Tzvete Dentchev, Darren M. Wilson, Velpandi Ayyavoo, and David B. Weiner. "Targeted antigen delivery to antigen–presenting cells including dendritic cells by engineered Fas-mediated apoptosis." Nature Biotechnology 18, no. 9 (September 2000): 974–79. http://dx.doi.org/10.1038/79470.

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Chatterjee, Bithi, Anna Smed-Sörensen, Lillian Cohn, Cécile Chalouni, Richard Vandlen, Byoung-Chul Lee, Jenifer Widger, Tibor Keler, Lélia Delamarre, and Ira Mellman. "Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells." Blood 120, no. 10 (September 6, 2012): 2011–20. http://dx.doi.org/10.1182/blood-2012-01-402370.

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Abstract Dendritic cells (DCs) can capture extracellular antigens and load resultant peptides on to MHC class I molecules, a process termed cross presentation. The mechanisms of cross presentation remain incompletely understood, particularly in primary human DCs. One unknown is the extent to which antigen delivery to distinct endocytic compartments determines cross presentation efficiency, possibly by influencing antigen egress to the cytosol. We addressed the problem directly and quantitatively by comparing the cross presentation of identical antigens conjugated with antibodies against different DC receptors that are targeted to early or late endosomes at distinct efficiencies. In human BDCA1+ and monocyte-derived DCs, CD40 and mannose receptor targeted antibody conjugates to early endosomes, whereas DEC205 targeted antigen primarily to late compartments. Surprisingly, the receptor least efficient at internalization, CD40, was the most efficient at cross presentation. This did not reflect DC activation by CD40, but rather its relatively poor uptake or intra-endosomal degradation compared with mannose receptor or DEC205. Thus, although both early and late endosomes appear to support cross presentation in human DCs, internalization efficiency, especially to late compartments, may be a negative predictor of activity when selecting receptors for vaccine development.

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Li, Zhenhua, Kai Dong, Yan Zhang, Enguo Ju, Zhaowei Chen, Jinsong Ren, and Xiaogang Qu. "Biomimetic nanoassembly for targeted antigen delivery and enhanced Th1-type immune response." Chemical Communications 51, no. 88 (2015): 15975–78. http://dx.doi.org/10.1039/c5cc06794d.

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Gallovic, Matthew D., Douglas G. Montjoy, Michael A. Collier, Clement Do, Barbara E. Wyslouzil, Eric M. Bachelder, and Kristy M. Ainslie. "Chemically modified inulin microparticles serving dual function as a protein antigen delivery vehicle and immunostimulatory adjuvant." Biomaterials Science 4, no. 3 (2016): 483–93. http://dx.doi.org/10.1039/c5bm00451a.

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Assani, Kaivon, Amy Neidhard-Doll, and Tarun Goswami. "Mechanical properties of nanoparticles in the drug delivery kinetics." Journal of Pharmaceutical and Biopharmaceutical Research 4, no. 1 (2022): 248–55. http://dx.doi.org/10.25082/jpbr.2022.01.002.

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Nanoparticle formulation is a recently developed drug delivery technology with enhanced targeting potential. Nanoparticles encapsulate the drug of choice and delivers it to the target via a targeting molecules (ex. antigen) located on the nanoparticle surface. Nanoparticles can even be targeted to deeply penetrating tissue and can be modeled to deliver drugs through the blood brain barrier. These advancements are providing better disease targeting such as to cancer and Alzheimer’s. Various polymers can be manufactured into nanoparticles. The polymers examined in this paper are polycaprolactone (PCL), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(glycolic acid) (PGA). The purpose of this study is to analyze the mechanical properties of these polymers to establish drug delivery trends and model pharmacokinetics and biotransport. We found that, in general, as the melting point, elastic modulus and tensile strength increases, the degradation rate also increases. PLA composite material may be an ideal polymer for drug delivery due to its good control of degradation.

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Cohn, Lillian, Bithi Chatterjee, Filipp Esselborn, Anna Smed-Sörensen, Norihiro Nakamura, Cécile Chalouni, Byoung-Chul Lee, et al. "Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation." Journal of Experimental Medicine 210, no. 5 (April 8, 2013): 1049–63. http://dx.doi.org/10.1084/jem.20121251.

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Human BDCA3+ dendritic cells (DCs), the proposed equivalent to mouse CD8α+ DCs, are widely thought to cross present antigens on MHC class I (MHCI) molecules more efficiently than other DC populations. If true, it is unclear whether this reflects specialization for cross presentation or a generally enhanced ability to present antigens on MHCI. We compared presentation by BDCA3+ DCs with BDCA1+ DCs using a quantitative approach whereby antigens were targeted to distinct intracellular compartments by receptor-mediated internalization. As expected, BDCA3+ DCs were superior at cross presentation of antigens delivered to late endosomes and lysosomes by uptake of anti-DEC205 antibody conjugated to antigen. This difference may reflect a greater efficiency of antigen escape from BDCA3+ DC lysosomes. In contrast, if antigens were delivered to early endosomes through CD40 or CD11c, BDCA1+ DCs were as efficient at cross presentation as BDCA3+ DCs. Because BDCA3+ DCs and BDCA1+ DCs were also equivalent at presenting peptides and endogenously synthesized antigens, BDCA3+ DCs are not likely to possess mechanisms for cross presentation that are specific to this subset. Thus, multiple DC populations may be comparably effective at presenting exogenous antigens to CD8+ T cells as long as the antigen is delivered to early endocytic compartments.

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Iwamura, Chie, Charles Benck, William Coley, Yi Liu, Yongge Zhao, Juan Antonio Quiel Esposito, and Kristin V. Tarbell. "Autoreactive T cells display altered CD25 expression that changes responses to low dose IL-2 and antigen delivery." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 127.21. http://dx.doi.org/10.4049/jimmunol.198.supp.127.21.

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Abstract Dendritic cells (DCs) are important for T cell tolerance induction and treatment of autoimmune diseases such as type 1 diabetes. Chimeric antibodies that deliver self-antigens to DCIR2+ DCs can delay but not completely prevent diabetes development in non-obese diabetic (NOD) mice. These DCIR2 antibodies induce T cell tolerance via antigen-specific deletion and anergy, but do not increase antigen-specific Foxp3+ regulatory T cells (Tregs). Because low dose (LD) IL-2 administration can preferentially expand Tregs, we asked if delivering antigens to tolerogenic DCIR2+ DCs along with IL-2 would boost antigen-specific Tregs and block autoimmunity. But, surprisingly, adding IL-2 did not increase efficacy of DC-targeted antigens to inhibit diabetes. To date, the effect of LD-IL-2 on autoreactive Treg and effector T cells has not been fully elucidated. By using tetramer staining to identify islet-specific CD4+ T cells in NOD mice, we now show the effects of LD-IL-2, with or without specific antigen delivery to DCIR2+ DCs, on both polyclonal and autoreactive effector and regulatory T cells. As expected, LD-IL-2 increased total Tregs, but autoreactive Tregs required addition of antigen and LD-IL-2 to elicit significant expansion. We found that islet-specific Tregs had lower CD25 expression compared to polyclonal Tregs, but islet-specific Foxp3− cells had higher CD25 expression. IL-2 increased activation and expansion of Foxp3− cells, and this effect was more pronounced for autoreactive cells after treatment with IL-2 + islet antigens. Therefore, IL-2, especially when combined with self-antigens, may not be an effective treatment for chronic autoimmunity, and increased Foxp3+ cells may not be a good biomarker for treatment efficacy.

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Saeed, Mesha, Sara Zalba, Ann Seynhaeve, Reno Debets, and Timo L. M. ten Hagen. "Liposomes targeted to MHC-restricted antigen improve drug delivery and antimelanoma response." International Journal of Nanomedicine Volume 14 (March 2019): 2069–89. http://dx.doi.org/10.2147/ijn.s190736.

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Shakya, Akhilesh Kumar, and Kutty Selva Nandakumar. "Antigen-Specific Tolerization and Targeted Delivery as Therapeutic Strategies for Autoimmune Diseases." Trends in Biotechnology 36, no. 7 (July 2018): 686–99. http://dx.doi.org/10.1016/j.tibtech.2018.02.008.

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Baert, Kim, Bruno G. de Geest, Riet de Rycke, André B. da Fonseca Antunes, Henri de Greve, Eric Cox, and Bert Devriendt. "β-glucan microparticles targeted to epithelial APN as oral antigen delivery system." Journal of Controlled Release 220 (December 2015): 149–59. http://dx.doi.org/10.1016/j.jconrel.2015.10.025.

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Hawiger, Daniel, Kayo Inaba, Yair Dorsett, Ming Guo, Karsten Mahnke, Miguel Rivera, Jeffrey V. Ravetch, Ralph M. Steinman, and Michel C. Nussenzweig. "Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo." Journal of Experimental Medicine 194, no. 6 (September 17, 2001): 769–80. http://dx.doi.org/10.1084/jem.194.6.769.

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Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

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Alarcon, Neftali Ortega, Maddy Jaramillo, Heidi M. Mansour, and Bo Sun. "Therapeutic Cancer Vaccines—Antigen Discovery and Adjuvant Delivery Platforms." Pharmaceutics 14, no. 7 (July 11, 2022): 1448. http://dx.doi.org/10.3390/pharmaceutics14071448.

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For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.

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Ji, Xiaoting, Haoyuan Lv, Xinxin Sun, and Caifeng Ding. "Green-emitting carbon dot loaded silica nanoparticles coated with DNA-cross-linked hydrogels for sensitive carcinoembryonic antigen detection and effective targeted cancer therapy." Chemical Communications 55, no. 100 (2019): 15101–4. http://dx.doi.org/10.1039/c9cc07831b.

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Amato, Robert J., and Mika Stepankiw. "Clinical Efficacy of TroVax in the Treatment of Progressive Castration-resistant Prostate Cancer." Clinical Medicine Insights: Oncology 6 (January 2012): CMO.S7654. http://dx.doi.org/10.4137/cmo.s7654.

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With approximately 240,890 new cases expected in 2011, prostate cancer remains the leading cause of non-melanoma cancer deaths in men. Immunotherapies using viral vector-based delivery systems targeting tumor-specific antigens are being studied. Viral vector-based delivery systems present tumor-targeted antigens (TAAs) to the immune system while breaking self-tolerance. Modified vaccinia ankara has been combined with the oncofetal antigen 5T4 to create TroVax for the treatment of castration-resistant prostate cancer (CRPC). The 5T4 antigen is highly expressed in a large number of carcinomas, including prostate cancer, but is rarely expressed in healthy tissue. TroVax has been demonstrated to be safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies in colorectal, renal cell, and prostate cancer. With minimal side effects and the ability to produce a strong immunogenic response, TroVax (MVA-5T4) is a viable addition to the treatment of prostate cancer.

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Feng, Haibo, Yangyang Feng, Lang Lin, Daiyan Wu, Qianqian Liu, Hangyu Li, Xinnan Zhang, et al. "Mannose Receptor-Mediated Carbon Nanotubes as an Antigen Delivery System to Enhance Immune Response Both In Vitro and In Vivo." International Journal of Molecular Sciences 23, no. 8 (April 11, 2022): 4239. http://dx.doi.org/10.3390/ijms23084239.

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Carbon nanotubes (CNTs) are carbon allotropes consisting of one, two, or more concentric rolled graphene layers. These can intrinsically regulate immunity by activating the innate immune system. Mannose receptors (MR), a subgroup of the C-type lectin superfamily, are abundantly expressed on macrophages and dendritic cells. These play a crucial role in identifying pathogens, presenting antigens, and maintaining internal environmental stability. Utilizing the specific recognition between mannose and antigen-presenting cells (APC) surface mannose receptors, the antigen-carrying capacity of mannose-modified CNTs can be improved. Accordingly, here, we synthesized the mannose-modified carbon nanotubes (M-MWCNT) and evaluated them as an antigen delivery system through a series of in vitro and in vivo experiments. In vitro, M-MWCNT carrying large amounts of OVA were rapidly phagocytized by macrophages and promoted macrophage proliferation to facilitate cytokines (IL-1β, IL-6) secretion. In vivo, in mice, M-MWCNT induced the maturation of dendritic cells and increased the levels of antigen-specific antibodies (IgG, IgG1, IgG2a, IgG2b), and cytokines (IFN-γ, IL-6). Taken together, M-MWCNT could induce both humoral and cellular immune responses and thereby can be utilized as an efficient antigen-targeted delivery system.

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Feng, Haibo, Xiaonong Yang, Linzi Zhang, Qianqian Liu, Yangyang Feng, Daiyan Wu, Yunjie Liu, and Jie Yang. "Mannose-Modified Chitosan Poly(lactic-co-glycolic acid) Microspheres Act as a Mannose Receptor-Mediated Delivery System Enhancing the Immune Response." Polymers 13, no. 13 (July 3, 2021): 2208. http://dx.doi.org/10.3390/polym13132208.

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The mannose receptor (MAN-R)-targeted delivery system is commonly used to deliver antigens to macrophages or immature dendritic cells (DCs) to promote the efficiency of antigen presentation. To maximize the enhancement effects of chitosan (CS) and induce an efficient humoral and cellular immune response against an antigen, we encapsulated ovalbumin (OVA) in poly(lactic-co-glycolic acid) (PLGA) microspheres (MPs) and conjugated it with MAN-modified CS to obtain MAN-R-targeting nano-MPs (MAN-CS-OVA-PLGA-MPs). The physicochemical properties, drug loading rate, and immunomodulation activity of MAN-CS-OVA-PLGA-MPs were evaluated. In vitro, MAN-CS-OVA-PLGA-MPs (80 μg mL−1) could enhance the proliferation of DCs and increase their phagocytic efficiency. In vivo, MAN-CS-OVA-PLGA-MPs significantly increased the ratio of CD3+CD4+/CD3+CD8+ T cells, increased CD80+, CD86+, and MHC II expression in DCs, and improved OVA-specific IgG, IgG1, IgG2a, and IgG2b antibodies. Moreover, MAN-CS-OVA-PLGA-MPs promoted cytokine (IFN-γ, IL-4, and IL-6) production in mice. Taken together, our results show that MAN-CS-OVA-PLGA-MPs may act by activating the T cells to initiate an immune response by promoting the maturation of dendritic cells and improving their antigen presentation efficiency. The current study provides a basis for the use of MAN-CS-OVA-PLGA-MPs as an antigen and adjuvant delivery system targeting the MAN-R on the surface of macrophages and dendritic cells.

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Gardner, Thomas J., Christopher M. Bourne, Megan M. Dacek, Keifer Kurtz, Manish Malviya, Leila Peraro, Pedro C. Silberman, et al. "Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery." Cancers 12, no. 8 (August 5, 2020): 2175. http://dx.doi.org/10.3390/cancers12082175.

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The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.

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Dobrovolskaia, Marina A. "Nucleic Acid Nanoparticles at a Crossroads of Vaccines and Immunotherapies." Molecules 24, no. 24 (December 17, 2019): 4620. http://dx.doi.org/10.3390/molecules24244620.

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Vaccines and immunotherapies involve a variety of technologies and act through different mechanisms to achieve a common goal, which is to optimize the immune response against an antigen. The antigen could be a molecule expressed on a pathogen (e.g., a disease-causing bacterium, a virus or another microorganism), abnormal or damaged host cells (e.g., cancer cells), environmental agent (e.g., nicotine from a tobacco smoke), or an allergen (e.g., pollen or food protein). Immunogenic vaccines and therapies optimize the immune response to improve the eradication of the pathogen or damaged cells. In contrast, tolerogenic vaccines and therapies retrain or blunt the immune response to antigens, which are recognized by the immune system as harmful to the host. To optimize the immune response to either improve the immunogenicity or induce tolerance, researchers employ different routes of administration, antigen-delivery systems, and adjuvants. Nanocarriers and adjuvants are of particular interest to the fields of vaccines and immunotherapy as they allow for targeted delivery of the antigens and direct the immune response against these antigens in desirable direction (i.e., to either enhance immunogenicity or induce tolerance). Recently, nanoparticles gained particular attention as antigen carriers and adjuvants. This review focuses on a particular subclass of nanoparticles, which are made of nucleic acids, so-called nucleic acid nanoparticles or NANPs. Immunological properties of these novel materials and considerations for their clinical translation are discussed.

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Salaheldin, Taher A., Dhruba J. Bharali, and Shaker A. Mousa. "Functionalized nano-targeted moieties in management of prostate cancer." Future Oncology 16, no. 13 (May 2020): 869–83. http://dx.doi.org/10.2217/fon-2019-0635.

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Multimodal properties of nanoparticles, such as simultaneously carrying drugs and/or diagnostic probes for site-specific delivery, make them excellent carriers for diagnosis and treatment of prostate cancer. Advantages are high permeability and selectivity to malignant cells to reduce systemic toxicity of chemotherapeutic drugs. Based on a review of current literature, the lack of efficient and highly specific prostate cancer cell targeting moieties is hindering successful in vivo prostate cancer-targeted drug delivery systems. Highly specific nano-targeting moieties as drug delivery vehicles might improve chemotherapeutic delivery via targeting to specific receptors expressed on the surface of prostate cancer cells. This review describes nano-targeting moieties for management of prostate cancer and its cancer stem cells. Descriptions of targeting moieties using anti-prostate-specific membrane antigen, aptamer, anti-cluster of differentiation 24/44, folic acid and other targeting strategies are highlighted. Current research results are promising and may yield development of next-generation nanoscale theragnostic targeted modalities for prostate cancer treatment.

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Arpit Rajaram Suralkar, Chaitanya Shahaji Khedkar, Nidhi R Zanwar, Chanchal C Chandak, and Shital J Gandhi. "Liposomes as a novel drug delivery system." GSC Biological and Pharmaceutical Sciences 20, no. 3 (September 30, 2022): 336–43. http://dx.doi.org/10.30574/gscbps.2022.20.3.0372.

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Liposome is a microparticulate colloidal vesicle, in which aqueous medium is surrounded by single or multiple concentric layers of phospholipids. Both hydrophilic & hydrophobic drug can be incorporated, water soluble drug being trapped in aqueous core and fat soluble drug in phospholipids. It offers controlled release, targeted drug delivery thus enhanced therapeutic efficacy and reduced dosing frequency. Several liposome based drug formulation are approved for clinical use and many are under extensive investigation. Therapeutically, these are used as carrier for drugs, viruses, bacteria, antigen, peptides (antibiotic), vaccines, genes and diagnostic agents. This review discusses about the method of production and extensive therapeutic potential of liposomes as carriers for targeted and controlled delivery.

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Hossain, Dewan Md Sakib, Cedric Dos Santos, Qifang Zhang, Anna Kozlowska, Hongjun Liu, Chan Gao, Dayson Moreira, et al. "Leukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity." Blood 123, no. 1 (January 2, 2014): 15–25. http://dx.doi.org/10.1182/blood-2013-07-517987.

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Key Points Blocking STAT3 in acute myeloid leukemia cells stimulates their TLR9-induced immunogenicity and antigen-specific activation of CD8+ T cells. Systemic delivery of CpG-Stat3 siRNA generates potent adaptive immune responses eradicating disseminated acute myeloid leukemia in vivo.

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Schnurr, Max, Qiyuan Chen, Amanda Shin, Weisan Chen, Tracey Toy, Corinna Jenderek, Simon Green, et al. "Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery." Blood 105, no. 6 (March 15, 2005): 2465–72. http://dx.doi.org/10.1182/blood-2004-08-3105.

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AbstractDendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.

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Morse, M., R. Chapman, T. Clay, T. Osada, A. Hobeika, J. Green, T. Davis, and T. Keler. "Antigen presenting cell (APC)-targeted hCGβ vaccine for cancer therapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3013. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3013.

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3013 Background: CDX-1307 is a novel vaccine approach designed to target antigens directly into the endocytic compartments of dendritic cells (DCs) and other professional APCs. The β subunit of human chorionic gonadotropin (hCGβ) is selectively over-expressed by a number of epithelial tumors and has been reported to correlate with stage of disease and prognosis. We have coupled this tumor-associated antigen to a human monoclonal antibody (B11) that targets mannose receptors on human dendritic cells and macrophages, and have demonstrated the efficacy of this approach in preclinical models using hCGβ-expressing tumors and cell lines. Methods: In this phase I, dose-escalating study, sequential cohorts of 6 patients with relapsed epithelial tumors receive 4 biweekly intradermal injections of CDX-1307 at either 0.3, 1.0 or 2.5 mg, or 2.5 mg concurrent with GM-CSF. Objectives: safety and tolerability; DLT, humoral and cellular immune response, and clinical activity. Results: Enrollment in the first three cohorts (n=18) is complete with no DLTs. Common potential treatment-related toxicities were injection site reaction (n=5) and fatigue/malaise (n=4), and were generally mild to moderate in severity. One transient Grade 3 generalized allergic reaction in the 1.0 mg cohort was suspected possibly related to either a nut allergy or CDX-1307. One mixed response was seen, with variable effects on circulating hCGβ. CDX-1307 localized to dermal macrophages and DCs in post-treatment biopsies. Conclusions: Administration of CDX-1307 is well tolerated and results in antigen localization in APCs of the skin. Immune Response and tumor impact are under evaluation. Further development includes systemic delivery that may provide antigen targeting to a broad APC population, and combination with immunostimulants to generate optimal immune responses. No significant financial relationships to disclose.

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Journal articles on the topic 'Targeted antigen delivery'

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