Evaluating single-domain antibodies as carriers for targeted vaccine delivery to the small intestinal epithelium

Bakshi, Shruti; Garcia, Raquel Sanz; Weken, Hans Van der; Tharad, Ashuwini; Pandey, S.; Juárez, Paloma; Virdi, Vikram; Devriendt, Bert; Cox, Eric; Depicker, Anna

doi:10.1016/j.jconrel.2020.01.033

Cited by 13 publications

(13 citation statements)

References 42 publications

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“…12,13 This approach is an extension of previously reported approaches for similar purposes with VHH-Fc ones. [14][15][16][17] Particularly interesting was the fact that VHHs are internalized thoroughly, [18][19][20][21] if their receptor targets are expressed at the surface of the cells, and obviously accessible from the outside. We thus wanted to combine, somehow, some features of the VHH together with those from antibodies.…”

Section: Introductionmentioning

confidence: 99%

Biochemistry, structure, and cellular internalization of a four nanobody‐bearing Fc dimer

et al. 2021

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VHH stands for the variable regions of heavy chain only of camelid IgGs. The VHH family forms a set of interesting proteins derived from antibodies that maintain their capacity to recognize the antigen, despite their relatively small molecular weight (in the 12,000 Da range). Continuing our exploration of the possibilities of those molecules, we chose to design alternative molecules with maintained antigen recognition, but enhanced capacity, by fusing four VHH with one Fc, the fragment crystallizable region of antibodies. In doing so, we aimed at having a molecule with superior quantitative antigen recognition (×4) while maintaining its size below the 110 kDa. In the present paper, we described the building of those molecules that we coined VHH2‐Fc‐VHH2. The structure of VHH2‐Fc‐VHH2 in complex with HER2 antigen was determined using electronic microscopy and modeling. The molecule is shown to bind four HER2 proteins at the end of its flexible arms. VHH2‐Fc‐VHH2 also shows an internalization capacity via HER2 receptor superior to the reference anti‐HER2 monoclonal antibody, Herceptin®, and to a simple fusion of two VHH with one Fc (VHH2‐Fc). This new type of molecules, VHH2‐Fc‐VHH2, could be an interesting addition to the therapeutic arsenal with multiple applications, from diagnostic to therapy.

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Section: Introductionmentioning

confidence: 99%

Biochemistry, structure, and cellular internalization of a four nanobody‐bearing Fc dimer

et al. 2021

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“…The targeting of vaccine antigens towards epithelial cells and antigen presenting cells might be a potential mechanism to increase the efficacy of oral vaccines by interacting with receptors that activate different signaling transduction pathways, circumventing the tolerogenic response and enhancing uptake (7,30,31). Our group has identified APN as an interesting target for oral antigen delivery (16)(17)(18). In this study, we evaluated the use of APN-targeted monoclonal antibodies and recombinant antibody constructs as a delivery system for vaccine antigens.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, oral administration of purified F4 fimbriae to piglets triggered protective SIgA responses (14). Moreover, delivery of antigens and microparticles to aminopeptidase N by different antibody formats facilitated their uptake by the small intestinal epithelium and elicited strong immune responses in piglets upon oral administration (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Antibody-Mediated Targeting of Antigens to Intestinal Aminopeptidase N Elicits Gut IgA Responses in Pigs

et al. 2021

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Many pathogens enter the host via the gut, causing disease in animals and humans. A robust intestinal immune response is necessary to protect the host from these gut pathogens. Despite being best suited for eliciting intestinal immunity, oral vaccination remains a challenge due to the gastrointestinal environment, a poor uptake of vaccine antigens by the intestinal epithelium and the tolerogenic environment pervading the gut. To improve uptake, efforts have focused on targeting antigens towards the gut mucosa. An interesting target is aminopeptidase N (APN), a conserved membrane protein present on small intestinal epithelial cells shown to mediate epithelial transcytosis. Here, we aimed to further optimize this oral vaccination strategy in a large animal model. Porcine APN-specific monoclonal antibodies were generated and the most promising candidate in terms of epithelial transcytosis was selected to generate antibody fusion constructs, comprising a murine IgG1 or porcine IgA backbone and a low immunogenic antigen: the F18-fimbriated E. coli tip adhesin FedF. Upon oral delivery of these recombinant antibodies in piglets, both mucosal and systemic immune responses were elicited. The presence of the FedF antigen however appeared to reduce these immune responses. Further analysis showed that F18 fimbriae were able to disrupt the antigen presenting capacity of intestinal antigen presenting cells, implying potential tolerogenic effects of FedF. Altogether, these findings show that targeted delivery of molecules to epithelial aminopeptidase N results in their transcytosis and delivery to the gut immune systems. The results provide a solid foundation for the development of oral subunit vaccines to protect against gut pathogens.

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“…Living delivery systems Recombinant bacteria [34][35][36][37][38][39][40][41][42][43][44] Viral vectors [45][46][47][48][49][50][51][52][53][54][55][56] Non-living delivery systems Virus-like particles [57] Micro-and nanoparticles [58][59][60] Lipid-based delivery systems [61][62][63][64][65][66][67][68][69] Nanogels [70] Targeted delivery M-cells Dectin-1 [71], GP2 [72], C5aR [73] Enterocytes FcRn [74] Aminopeptidase N [60,[75][76][77][78][79]…”

Section: Delivery Systemsmentioning

confidence: 99%

“…However, antibody-mediated targeting to porcine APN, independent of this carbohydrate moiety, also triggered epithelial transcytosis. Oral administration to piglets of different APN-specific antibody formats (polyclonal, monoclonal as well as VHH-based antibody constructs) elicited systemic and intestinal antibody responses, further validating APN as an interesting receptor for targeted delivery of vaccine antigens [ 76 , 79 ]. The antibody-mediated targeting of antigen-loaded microparticles towards APN also showed promising results, improving uptake and subsequent antigen-specific immune responses upon oral administration [ 60 ].…”

Section: Oral Vaccination Strategiesmentioning

confidence: 99%

Advances in Oral Subunit Vaccine Design

2020

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Many pathogens invade the host at the intestinal surface. To protect against these enteropathogens, the induction of intestinal secretory IgA (SIgA) responses is paramount. While systemic vaccination provides strong systemic immune responses, oral vaccination is the most efficient way to trigger protective SIgA responses. However, the development of oral vaccines, especially oral subunit vaccines, is challenging due to mechanisms inherent to the gut. Oral vaccines need to survive the harsh environment in the gastrointestinal tract, characterized by low pH and intestinal proteases and need to reach the gut-associated lymphoid tissues, which are protected by chemical and physical barriers that prevent efficient uptake. Furthermore, they need to surmount default tolerogenic responses present in the gut, resulting in suppression of immunity or tolerance. Several strategies have been developed to tackle these hurdles, such as delivery systems that protect vaccine antigens from degradation, strong mucosal adjuvants that induce robust immune responses and targeting approaches that aim to selectively deliver vaccine antigens towards specific immune cell populations. In this review, we discuss recent advances in oral vaccine design to enable the induction of robust gut immunity and highlight that the development of next generation oral subunit vaccines will require approaches that combines these solutions.

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Evaluating single-domain antibodies as carriers for targeted vaccine delivery to the small intestinal epithelium

Cited by 13 publications

References 42 publications

Biochemistry, structure, and cellular internalization of a four nanobody‐bearing Fc dimer

Biochemistry, structure, and cellular internalization of a four nanobody‐bearing Fc dimer

Antibody-Mediated Targeting of Antigens to Intestinal Aminopeptidase N Elicits Gut IgA Responses in Pigs

Advances in Oral Subunit Vaccine Design

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