Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment

Figures & data

Table 1 Related Fusion Protein Analogs for the Treatment of Diabetes

Category	Drug Name	Trade Name	Structure	Ligand	Half-Life	Research Status	Major Adverse Reactions	References
IgG Fc Fusion proteins	Dulaglutide	Trulicity	GLP-1 analogue - IgG4Fc	GLP-1R	5 days	Listed (FDA 2014)	Gastrointestinal adverse reactions	[9–12]
	Efpeglenatide		Exendin-4 analogue - IgG4Fc	GLP-1R	5.6 to 7.5 days	Clinical Phase 3 trial	Gastrointestinal adverse reactions	[13]
	Basal Insulin Fc /Insulin efsitora alfa		Insulin analogue - IgG2Fc	Insulin receptor	14 days	Clinical Phase 2 trial	Low blood sugar	[14]
	Etanercept	Enbrel	TNFRII- IgG1Fc	Membrane TNFR	3–5.5 days	Listed (FDA 1998) but for T1DM treatment in a small pilot study	Injection site reaction and infections	[15,16]
	Abatacept	Orencia	CTLA-4- IgG1Fc	B7	2 weeks	Listed (2005 FDA) but for T1DM treatment in clinical Phase 2 trial	Upper respiratory tract infection and disgusting	[17,18]
	sgp130Fc /Olamkicept		gp130- IgG1Fc	sIL-6R	4.7 days	Clinical phase 2 trial	Seasonal upper respiratory tract infections and skin diseases	[19]
	Alefacept	Amevive	LFA-3 - IgG1Fc	CD2	12 days	Listed (2003 FDA) but for T1DM treatment in clinical phase 2 trial	Low blood sugar and infection	[20,21]
	Rilonacept	Arcalyst	IL-1R- IgG1Fc	IL-1α, IL-1β	6–8 days	Listed (2008 FDA) for T1DM treatment in clinical Phase 1 trial	Injection site reaction and upper respiratory tract infections	[22]
Albumin Fusion proteins	Albiglutide	Tanzeum	GLP-1 analogue-albumin	GLP-1R	6–8 days	Listed (FDA 2014)	Gastrointestinal adverse reactions and pancreatitis	[23,24]
	Albulin		Insulin-albumin	Insulin receptor	50 hours	Rats		[25,26]
Transferrin fusion protein	ProINS-TF		Proinsulin-Transferrin	Insulin receptor	7.29 hours	Rats		[27]

Figure 1 The signaling pathways and targets of drug action in normal humans after glucose uptake. In normal humans, blood glucose rises after food intakes and stimulates insulin secretion from pancreatic beta cells. Insulin first binds to the insulin receptor (IR) on the cell surface, which phosphorylates the insulin receptor itself, and the activated IR promotes phosphorylation of the tyrosine structural domain on the insulin receptor substrate (IRS), followed by signal transfer to the downstream PI3K/Akt2 pathway to amplify its active effect, and the activated Akt in turn continues to phosphorylate downstream effector molecules, including Rab-GTPase-activating protein, which ultimately translocates glucose transporter 4 (Glut-4)-vesicles from the cytosol to the cell membrane surface, regulating cellular glucose uptake. GLP-1 is known to inhibit glucagon secretion and promote insulin secretion. Dulaglutide, Albiglutide and Efpeglenatide, which are GLP-1 RAs, can lower blood glucose through both processes. Il-6 and TNF-α activation decreases the tyrosine kinase activity of insulin and impedes insulin-mediated glucose uptake in skeletal muscle and glucose uptake by adipocytes, both corresponding to the antagonists Olamkicept and Etanercept, which can block this pathway to achieve a lowering effect on blood glucose.

Abbreviations: IRS1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3 kinase, AKT, protein kinase B; Rab-GTP, Rab-GTPase-activating protein; GLUT4, glucose transporter 4.

Table 2 Types of Long-Acting Drugs

Category		Strengths	Weaknesses	References
Protein binding	Fc fusion	High homology	Expensive, potential immunogenicity, injectable use only	[48]
	Albumin binding	Low immunogenicity	Expensive and injectable use only	[48]
	Transferrin binding	Oral properties, low price and easily production	Unlisted and insufficient research	[48]
Other bio-molecule binding	PEGylation	Popular, safe, good solubility	Non-biodegradable, immunogenic and injured renal tubular epithelium	[48,58,59]
	Glycosylation	High stability	Close production monitor	[60–62]
Nanoparticle mediated		Oral properties, high stability, good biocompatibility and efficient bio-barrier penetration	Unpredictable drug clearance rate, nano-toxicity	[48,63–65]

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