A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease

Hu, Xiaozhi; Fan, Jiajun; Ma, Qianqian; Liu, Han; Cao, Ziping; Chen, Xu; Luan, Jingyun; Jing, Guangjun; Nan, Yanyang; Wu, Tao; Zhang, Yuting; Wang, Hanqi; Zhang, Yuanzhen; Ju, Dianwen

doi:10.1186/s12951-022-01456-z

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…Nanobodies containing only a heavy chain variable region (VHH) but still retain antigen specificity and high affinity 523 have proven their value in cancer therapy and diagnosis in recent years. 524 – 526 Two p53-binding nanobodies, Nb3 and Nb139, were obtained by immunization and panning procedures. 527 Nb3 binds to the “structural mutations” R175H and R282W, and Nb139 binds to both wild-type and mutant p53, inhibiting the transcriptional capacity of p53.…”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

157

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The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the “guardian of the genome”. Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an “undruggable” target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.

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Section: Structure-based P53 Targetingmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

157

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“…Although transient mild elevations in ALT were observed with ARO-ANG3 in a small number of subjects, these cases were associated with use of concomitant hepatotoxic medications and were self-limited. Hepatic steatosis has not been reported in carriers of ANGPTL3 loss-of-function variants 6,[8][9][10]20 and animal studies support reduction of liver fat with ANGPTL3 inhibition 22,23 . Therefore, the increase in liver fat reported with vupanorsen may be molecule-specific or may be due to use of higher and more frequent ASO dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Manuscript: AROANG1001: RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in serum triglyceride and non-HDL-cholesterol concentrations: a Phase 1 trial of ARO-ANG323 …”

mentioning

confidence: 99%

RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in serum triglyceride and non-HDL-cholesterol concentrations: first human results with ARO-ANG3

Watts

Schwabe

Scott

et al. 2022

Preprint

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Elevated triglycerides and non-HDL-cholesterol (C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). AROANG3 is a RNA interference therapy targeting hepatocyte production of angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This Phase 1 trial (NCT03747224) investigated single and repeat doses of AROANG3 in healthy volunteers and repeat doses in subjects with hepatic steatosis. AROANG3 was well tolerated without adverse changes in liver fat in steatotic subjects. In healthy volunteers, ARO-ANG3 produced reductions in ANGPTL3 (mean − 45% to -78%) 12 weeks post-dose. Concurrent reductions in triglycerides (median 34% to 54%) and nonHDL-C (mean 18% to 29%) were observed with the 3 highest doses. Reduced LDL-C was seen with repeat dosing. The data support ANGPTL3 as a potential therapeutic target for treatment of ASCVD.

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“…For vaccine design, those immunogenic antigens expressed in soluble forms by virus vectors can be fused to the Fc domain to further enhance the immunogenicity. In addition, biofuncational proteins, such as cytokines, receptors, and antibody fragments, fused to the Fc [38][39][40] and expressed by virus vectors, represent a promising means for targeted delivery of these macromolecules in vivo.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Fc-fusion Protein by a Recombinant Newcastle Disease Virus Vector

Feng

Deng

et al. 2022

Appl Biochem Biotechnol

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Fc-fusion proteins (FCPs), a new generation biological medicine, have revolutionized the practice of medicines that treat diseases. However, complex manufacturing techniques are required for FCP production, casting the affordability and accessibility issues in low-and middle-income economies (LMIEs). Virus-vectored system may serve as a simple and cost-effective platform for FCP delivery. As a proof-of-concept study, Newcastle disease virus (NDV), a widely-used vector for vaccine generation, was used as a vector to express and deliver a model FCP composed of the hemagglutinin (HA) and IgG Fc. A recombinant NDV expressing the HA-Fc fusion protein was generated using reverse genetics, which had comparable replication and virulence to the parental virus. High levels of expression of soluble HA-Fc were detected in cell culture and embryonated chicken eggs inoculated with the recombinant NDV. In addition, the recombinant NDV replicated in the lung of mouse, delivering the HA-Fc protein to this organ. The HA-Fc expressed by NDV specifically bound to murine FcγRI, which was dependent on the presence of the Fc tag. The recombinant NDV induced high vector-specific antibody response, whereas it failed to elicit H7N9specific antibody immunity in mice. The absence of HA-specific antibodies may be attributed to deficient incorporation of the HA-Fc protein into NDV virion particles. Our results indicated that NDV may be potentially used as a vector for FCP expression and delivery. This strategy may help to enhance the affordability and equal accessibility of FCP biological medicines, especially in LIMEs. Keywords Expression • Delivery • Fc-fusion protein • Virus vector • Newcastle disease virusZenglei Hu and Jianing Feng have equal contribution.

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A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease

Cited by 11 publications

References 53 publications

Targeting p53 pathways: mechanisms, structures and advances in therapy

Targeting p53 pathways: mechanisms, structures and advances in therapy

RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in serum triglyceride and non-HDL-cholesterol concentrations: first human results with ARO-ANG3

Delivery of Fc-fusion Protein by a Recombinant Newcastle Disease Virus Vector

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