Novel Anti-Inflammatory Approaches to COPD

Figures & data

Table 1 Therapies That Inhibit Recruitment and Activation of the Cellular Components of Inflammation in COPD

Class	Target	Drug	Clinical Development
PDE inhibitors	PDE4	Tanimilast	Phase 3
	PDE3/4	Ensifentrine	Phase 3
CXCR2 antagonists	CXCR2	Danirixin	Phase 2 (discontinued)
	CXCR1/2	Navarixin	Phase 2 (discontinued)
		Ladarixin	Phase 1
p38 MAPK inhibitors	p38α	CHF6297	Phase1/2
		Acumapimod	Phase 2
	p38α/β	Losmapimod	Phase 2 (discontinued)
		AZD7624	Phase 2 (discontinued)
	p38α/γ	RV568	Phase 2
	p38, Src and Syk kinases	PUR1800	Phase 1b
PI3K inhibitors	PI3Kδ	Nemiralisib	Phase 2 (discontinued)
	PI3Kγδ	AZD8154	Phase 1 (discontinued)
		RV1729	Phase 1
	Undisclosed	CHF6523	Phase 1
Selectin antagonists	E-, L-, and P-selectin	Bimosiamose	Phase 2 (discontinued)
Anti-IL-17A mAbs	IL-17A	CNTO 6785	Phase 2
Anti-IL-5 mAbs	IL-5	Mepolizumab	Phase 3
	IL-5Rα	Benralizumab	Phase 3
Anti-IL13/anti-IL4 mAbs	IL-13	Lebrikizumab	Phase 2
	IL-4R	Dupilumab	Phase 3
Anti-TSLP	TSLP	Tezepelumab.	Phase 2
Anti-IL-33 mAbs	IL-33	Itepekimab	Phase 3
		Tozorakimab	Phase 3
	ST2	Astegolimab	Phase 2

Abbreviations: CXCR2, CXC chemokine receptor 2; IL, interleukin; IL-4R, IL-4 receptor; IL-5Rα, IL-5 receptor α; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinases; PDE, phosphodiesterase; PI3K, phosphoinositide 3-kinase; ST2, tumour suppressor protein 2; TSLP, Thymic stromal lymphopoietin.

Figure 1 Effect of PDE inhibition in COPD. Combined inhibition of PDE3 and PDE4 provides additive and synergistic anti-inflammatory and bronchodilator effects when compared to PDE3 or PDE4 inhibition alone. It also improves mucociliary clearance. The primary PDE implicated in the activity of the given cell is shown in red.

Figure 2 The role of p38 MAPK in the pathobiology of COPD. At the level of alveolar macrophages and other inflammatory cells, airborne pollutants, cigarette smoke, and microbial pathogens activate p38 MAPK. The p38 signaling pathway leads to increased cytokine and chemokine production, particularly interleukin (IL)-1β, IL-8, and tumor necrosis factor-α (TNF-α), which are associated with the neutrophilic endotype of COPD. Therefore, inhibiting p38 MAPK may be an effective treatment for patients with COPD.

Figure 3 Monoclonal antibodies targeting T2 cytokines in COPD.

Abbreviations: ICL2, group 2 innate lymphoid cells; IL-4Rα, interleukin-4 receptor subunit α; IL-5Rα, interleukin-5 receptor subunit α; IL-13Rα, interleukin-13 receptor subunit α1.

Figure 4 Targeting alarmins in COPD.

Abbreviations: DC, dendritic cell; EGFR, epidermal growth factor receptor; ILC2, group 2 innate lymphoid cells; IL-1RAP, IL-1 receptor accessory protein; IL-33red, reduced IL-33; IL-33ox, oxidated IL-33; MC, mast cell; RAGE, receptor for advanced glycation end products; ST2, suppression of tumorigenicity 2; TSLP, thymic stromal lymphopoietin; TSLPR, TSLP receptor.

Table 2 Therapies That Antagonize the Products of the Cellular Components of Inflammation in COPD

Class	Target	Drug	Clinical Development
MMP inhibitors	MMP-12	V85546	Phase 1 (discontinued)
		FP-025	Phase 1 (asthma)
	MMP-9	Andecaliximab	Phase 1
	MMP-9/12	AZD1236	Phase 2 (discontinued)
NE inhibitors	NE	Alvelestat	Phase 2 (AATD)
		CHF6333	Phase 1
		BAY 85-8501	Phase 2 (AATD)
		Lonodelestat	Phase 1 (cystic fibrosis)
		Unfractionated heparin	Phase 2b
DPP1 inhibitors	DPP1	GSK2793660	Phase 1 (discontinued)
		Brensocatib	Phase 3 (bronchiectasis)
AAT	AATD	AAT-MP	Phase 3
		INBRX-101	Phase 1
		Inhaled AAT	Phase 3
		Subcutaneous AAT	Phase 1
		VX-864	Phase 2

Abbreviations: AAT, α1-antitrypsin, AATD, AAT deficiency; DPP1, dipeptidyl peptidase 1; MMP, matrix metalloproteinase; NE, neutrophil elastase.

Figure 5 Proteolytic interplay between α1-antitrypsin (AAT), matrix metalloproteinases (MMPs) and neutrophil elastase (NE). Several proteases, including neutrophil elastase (NE) and MMP-9 and MMP-12, are involved in COPD. Therefore, inhibiting a single enzyme with a NE inhibitor or a MMP inhibitor may not have a significant therapeutic impact. AAT inhibits NE and reduces macrophage MMP-12 synthesis.