Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

Chodorge, Matthieu; Celeste, Anthony J.; Grimsby, Joseph; Konkar, Anish; Davidsson, Pia; Fairman, David; Jenkinson, Lesley; Naylor, Jacqueline; White, N. E.; Seaman, Jonathan; Dickson, Karen; Kemp, Benjamin; Spooner, Jennifer; Rossy, Emmanuel; Hornigold, David C.; Trevaskis, James L.; Bond, Nicholas J.; London, Timothy B.; Buchanan, Andrew; Vaughan, Tristan J.; Rondinone, Cristina M.; Osbourn, Jane

doi:10.1038/s41598-018-35869-4

Cited by 18 publications

(10 citation statements)

References 47 publications

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“…The combination of GLP-1 and anti-PCSK9 antibodies, like the GLP-1/FGF21 combinations, has great promise in diabetic patients at risk of cardiovascular disease due to effects on hypercholesterolemia. A pharmaceutically-optimized GLP-1/anti-PCSK9 antibody was reported to have potent weight lowering efficacy in obese rodents and to have potent effects to lower cholesterol in cynomolgous monkeys [949]. In a recent phase I clinical study, treatment of overweight and obese patients with GLP-1/anti-PCSK9 decreased LDL cholesterol but failed to improve glucose metabolism [950].…”

Section: Pharmacological Use Of Glp-1 Analogs To Treat Obesity and DImentioning

confidence: 99%

Glucagon-like peptide 1 (GLP-1)

Müller¹,

Finan²,

Bloom³

et al. 2019

Molecular Metabolism

1,141

861

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BackgroundThe glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.Scope of reviewIn this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.Major conclusionsSince its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

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Section: Pharmacological Use Of Glp-1 Analogs To Treat Obesity and DImentioning

confidence: 99%

Glucagon-like peptide 1 (GLP-1)

Müller¹,

Finan²,

Bloom³

et al. 2019

Molecular Metabolism

1,141

861

View full text Add to dashboard Cite

show abstract

“…Several distinct pharmacophores can be attached to the dendrimer surface to design heterogenic multivalent compounds that display synergistic polypharmacology. For example, PCSK9 inhibitors and GLP‐1 analogues have been investigated as a co‐treatment for Type 2 diabetes, [50,51] and PCSK9 inhibitors have recently been shown to enhance the efficacy of immune checkpoint therapeutics such as PD‐1 inhibitors for treating cancer [52] . Dendrimers can also be designed to address other limitations of peptides such as short circulating half‐lives in vivo .…”

Section: Resultsmentioning

confidence: 99%

Increased Valency Improves Inhibitory Activity of Peptides Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

et al. 2021

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a clinically validated target for treating hypercholesterolemia. Peptide‐based PCSK9 inhibitors have attracted pharmaceutical interest, but the effect of multivalency on bioactivity is poorly understood. Here we designed bivalent and tetravalent dendrimers, decorated with the PCSK9 inhibitory peptides Pep2‐8[RRG] or P9‐38, to study relationships between peptide binding affinity, peptide valency, and PCSK9 inhibition. Increased valency resulted in improved PCSK9 inhibition for both peptides, with activity improvements of up to 100‐fold achieved for the P9‐38‐decorated dendrimers compared to monomeric P9‐38 in in vitro competition binding assays. Furthermore, the P9‐38‐decorated dendrimers showed improved potency at restoring functional low‐density lipoprotein (LDL) receptor levels and internalizing LDL in the presence of PCSK9, demonstrating significant cell‐based activity at picomolar concentrations. This study demonstrates the potential of increasing valency as a strategy for increasing the efficacy of peptide‐based PCSK9 therapeutics.

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“…The complementarity-determining regions (CDRs) located close to the N-terminus of the antibody is responsible for antigen recognition. Incorporation of penetratin at the N-terminus of anti-HER2 mAb may have blocked its HER2 binding ability by generating steric hindrance or directly interfering with the folding of CDR structure (Chodorge et al, 2018). As a result,…”

Section: Flow Cytometry To Characterize the Specific Binding Of Wild-mentioning

confidence: 99%

Engineering a Cell-Penetrating Anti-HER2 Monoclonal Antibody for Efficient Delivery of Gold Nanoparticles into Cancer Cells To Enhance X-Ray Cancer Radiation Therapy

Guo¹,

Hawkins²,

Wu³

2020

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Gold nanoparticles (GNPs) can create heat and free radicals after absorbing high energy photons from radiation. This light absorptive property has been utilized in cancer radiotherapy to produce highly localized heating and destroy cancer cells. For specific tumor accumulation, GNPs can be attached to monoclonal antibodies (mAbs) that recognize cell surface proteins overexpressed in certain types of cancer. One of these surface receptors is HER2, which is overexpressed in 20-25% of breast cancers and, therefore, constituted a suitable target for such mAb-driven GNP tumor localization. However, many mAbs cannot cross the cell membrane efficiently. To enable the efficient shuttling of GNPs into cancer cells, protein engineering technology was implemented to fuse penetratin, a cell-penetrating peptide (CPP), to the C-terminus of a wide-type anti-HER2 antibody heavy chain, generating a cell-penetrating mAb specific to the HER2 receptor. One of the recombinant mAbs (mAb-2CPP) completely preserved the HER2-binding activity and could promote the internalization of the antibody into MCF-7 and PC3 cancer cells that express HER2 on the cell surface. Both cell lines were then treated with GNPs conjugated to wild-type mAb (mAb-GNP) or mAb-CPP fusion (mAb-2CPP-GNP). The MAb-2CPP-GNP complex generated a higher mortality rate than mAb-GNP, likely due to more accumulation of GNPs in the cells. The study also investigated the interaction between X-ray radiation and GNPs, demonstrating that GNPs augmented the efficacy of X-ray radiation. Thus, a much lower dose of radiation could be used to generate a similar cell mortality rate. More GNPs were carried by mAb-2CPP into cancer cells and increased the cell mortality rate in a dose-dependent manner. Thus, an effective cell-penetrating antibody could promote the delivery of GNPs into target cancer cells and augment the efficacy of cancer radiotherapy with reduced side effects to patients.

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Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

Cited by 18 publications

References 47 publications

Glucagon-like peptide 1 (GLP-1)

Glucagon-like peptide 1 (GLP-1)

Increased Valency Improves Inhibitory Activity of Peptides Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Engineering a Cell-Penetrating Anti-HER2 Monoclonal Antibody for Efficient Delivery of Gold Nanoparticles into Cancer Cells To Enhance X-Ray Cancer Radiation Therapy

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