Table 3.

Summary of disease conditions, being potential targets for DASH inhibition or modulated by anti‐DPP4‐mononuclear antibody (mAb) and/or anti‐FAP‐mAb 7, 9, 10, 13, 30, 52, 121, 123, 124, 128, 129, 146, 147, 148, 149, 150, 151.

Target disease	Effect of inhibitor	Development stage	Comments	Inhibitor/mAb
Type 2 diabetes	Inhibition of incretin deactivation, improvement of postprandially stimulated insulin secretion and glucose tolerance	FDA approved: Sitagliptin, Saxagliptin, Linagliptin EMEA: Vildagliptin Japan: Alogliptin Korea: Gemigliptin	Many pharmaceutical companies are targeting DPP4 inhibition	Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Ondero) Vildagliptin (Galvus) Alogliptin (Nesina)
Tumours	Prevents spreading of metastases, inhibits tumour migration and angiogenesis by inhibiting FAP Inhibition of DPP8 + DPP9: ⇑ IL‐β ⇒ ⇑ cytokines + ⇑ chemokines ⇒ ⇑ neutrophils, ⇑ T‐lymphocytes, ⇑ macrophages	Phase III: FDA put on hold Phase II studies: Melanomas	Disapproved treatment on lung and pancreas cancer Clinical trials for melanomas	Talabostat (PT‐100) (Val‐boroPro) Discontinued
	Cell‐specific suppression of stromal tumours expression high levels of FAP	Human Clinical Phase I Animal model	F19‐antibody radio‐labelled chemotherapy	FAP‐mAbF19 Oral DNA vaccine against FAP
	Prevents spreading of metastases, inhibition of tumour migration and angiogenesis	Cell culture, animal models	Hetero‐dimerization with FAP involved	DPP4‐mAb 1F7 Pro‐boroPro
	Anti‐cancer effects and tumour cytotoxicity	Cell culture, animal models	Z‐GP‐Dox, an FAP‐based doxorubicin prodrug	Z‐GP‐Dox with, systemically delivered via mixed nanomicelles
	Potent anti‐tumour effects by increased levels of natural killer cells and DCs as well as making murine and human tumour cells more sensitive to antigen‐specific CTL killing	Cell culture, animal models	Pan inhibitor of DASH	ARI‐4175 in combination with a recombinant viral or dendritic cell (DC)‐based tumour‐cell vaccine
Multiple sclerosis	Suppression of EAE, involves Th17 cells	Animal experiments,human primary cell culture	Autoimmune disease	Lys[Z(NO2)]‐Pyr PETIR‐001
Psoriasis	Reduction of keratinocyte hyperproliferation, involves Th17 cells	Cell culture, animal models, preclinical studies	Autoimmune disease	Lys[Z(NO2)]‐Thia Lys[Z(NO2)]‐Pyr P32/98 PETIR‐001
Colitis	Suppression of GLP‐2 inactivation	Cell culture, animal models	DPP4, DPP8 and DPP2 may be involved	P32/98 PETIR‐001
IBD	Suppression of GLP‐2 inactivation, involves Th17 cells	Cell culture, animal models	DPP4 involved	P32/98 PETIR‐001
Rheumatoid arthritis	Suppression of symptoms via inhibition of DPP4 + FAP (L‐glutamyl L‐boroproline)	Animal models	DPP4 + DASH inhibition ⇒ PT of CD45 inhibition FAP involved	Lys[Z(NO2)]‐Thia Lys[Z(NO2)]‐Pyr TMC‐2A TSL‐225 L‐glutamyl L‐boroproline
Anxiety/stress	Suppression of NPY cleavage decreases anxiety	Effective in animal models (rats)	Suggested to mainly involve NPY + DPP4	P32/98
Psychosis/schizophrenia	DPP4 inhibitor blocks mescaline‐induced scratching + amphetamine‐induced hyperactivity Haloperidol ⇑ Kv4/DPP6 ⇒ ⇓ tardive dyskinesia	Effective in animal models (mice)	May also involve endomorphin‐1/2 Haloperidol ⇑ Kv4/DPP‐6	AMAC (DPP4) Haloperidol (DPP‐6)
Graft rejection	Suppression of graft rejection	Animal experiments		Pro‐Pro diphenyl‐phosphonate ester (prodipine)
Autoimmune disease	General immunosuppressive effects, involves Th17 cells	Cell culture, animal models	High doses necessary Dual inhibition of DPP4 and AP N (PETIR‐001)	Lys[Z(NO2)]‐Thia Lys[Z(NO2)]‐Pyr Ala‐boroPro Pro‐boroPro PETIR‐001
Acne	Inhibitors suppressed proliferation and IL‐2 production of Propionibacterium acnes‐stimulated T cells ex vivo + ⇓ TGF‐β	Cell culture	Dual inhibition of DPP4 and AP N (PETIR‐001)	Lys[Z(NO2)]‐Thia Lys[Z(NO2)]‐Pyr PETIR‐001
T cell lymphoid malignancies	Enhanced cell cycle arrest at the G1‐S checkpoint, resulting in increased p21 expression	Cell culture, animal models	Influences survival and de‐novo tumour growth	DPP4‐mAb 1F7 Diprotin A Val‐Pyr
B‐CCL	Prognostic marker + drug target	Ex‐vivo apoptosis assay	DPP2 inhibition	AX8819
AIDS	Suppression of SDF‐α cleavage, suppression of gp 120 and DPP4 interaction	Cell culture	Mechanism not fully understood	Phe‐Pyrr‐2‐CN Arg(PMC)‐ Pyrr‐2‐CN
Fibrinolysis	Suppression of α‐anti‐plasmin of cleavage	In‐vivo clotting	Involves FAP	Acetyl‐Arg‐(8‐amino‐3,6‐dioxaoctanoic acid)‐D‐Ala‐L‐boroPro
Wound‐healing	Promotion of wound‐healing	Cell culture	Heteromeric complex of DPP4 with FAP involved	DPP4‐mAbE26 DPP4‐mAbE19 DPP4‐mAbE3

Red text: inhibitor admitted or disapproved by a regulatory authority. PT, phosphatase activity.