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Table 4 Published disease specific “Un-lock” proteases

From: Ab locks for improving the selectivity and safety of antibody drugs

Disease

Protease expression (Refs.)

Example of applicable Ab drugs

Oncology

 Lung cancer

MMP-2 [17], MMP-13 [144], MMP-14 [49], Cathepsin B [76, 163, 184], Cathepsin H [151], Cathepsin S [83], ADAM-8 [68], ADAM-9 [117], ADAM-15 [150], ADAM-17 [117], ADAM-28 [122]

• Nivolumab/Pembrolizumab (anti-PD-1 Ab)

• Atezolizumab/Durvalumab (anti-PD-L1 Ab)

• Necitumumab (anti-EGFR Ab)

• Bevacizumab (anti-VEGF-A Ab)

• Ramucirumab (anti-VEGFR2 Ab)

 Colorectal cancer

MMP-2 [49], MMP-7 [26], MMP-9 [52, 197], MMP-13 [189], Cathepsin B [1, 177], Cathepsin L [1, 177], Cathepsin S [57], ADAM-10 [50], ADAM-12 [117], ADAM-17 [12], uPA [159]

• Cetuximab/Panitumumab (anti-EGFR Ab)

• Bevacizumab (anti-VEGF-A Ab)

• Ramucirumab (anti-VEGFR2 Ab)

• Ipilimumab (anti-CTLA-4 Ab)

• Nivolumab/Pembrolizumab (anti-PD-1 Ab)

 Breast Cancer

MMP-2 [49, 138], MMP-9 [49, 138], MMP-13 [141], MMP-14 [49], Cathepsin B [46, 48, 62, 84, 120, 158, 174], Cathepsin C [123], Cathepsin L [46, 126, 174], Cathepsin S [153], ADAM-9 [121], ADAM-12 [117], ADAM-15 [86], ADAM-17 [107], ADAM-28 [112], uPA [40, 96, 162]

• Trastuzumab/Trastuzumab emtansine (T-DM1)/Pertuzumab (anti-HER2 Ab)

• Atezolizumab (anti-PD-L1 Ab)

Autoimmune disorders

 Rheumatoid arthritis (RA)

MMP-2 [16], MMP-3 [9, 164, 194], MMP-9 [16],

• Adalimumab/Infliximab/Golimumab/Certolizumab pegol (anti-TNF-α Ab)

• Sarilumab/Tocilizumab (anti-IL-6R Ab)

• Rituximab (anti-CD20 Ab)

• Secukinumab (anti-IL-17A Ab)

 Psoriasis

MMP-1 [160], MMP-2 [45, 157, 160], MMP-3 [25], MMP-7 [109], MMP-8 [38], MMP-9 [5, 14, 45, 157, 160], MMP-12 [160, 167], MMP-14 [45], MMP-15 [45], MMP-19 [166], MMP-26 [167], MMP-28 [196], ADAM-10 [109], ADAM-12 [109], ADAM-17 [75], ADAM-33 [3, 198]

• Adalimumab/Infliximab (anti-TNF-α Ab)

• Efalizumab (anti-CD11a Ab)

• Ustekinumab (anti-IL-12/23 Ab)

• Secukinumab/Ixekizumab (anti-IL-17A Ab)

• Brodalumab (anti-IL-17R Ab)

• Guselkumab/Tildrakizumab/Risankizumab (anti-IL-23 p19 Ab)

 Multiple sclerosis (MS)

MMP-2 [7], MMP-7 [31, 92], MMP-9 [7, 31, 32, 56, 58, 89, 92]

• Natalizumab (anti-α4 integrin Ab)

• Alemtuzumab (anti-CD52 Ab)

• Ocrelizumab (anti-CD20 Ab)

• Daclizumab (anti-CD25 Ab)

Inflammatory diseases

 Chronic obstructed pulmonary disease (COPD)

MMP-1 [139], MMP-7 [155], MMP-8 [139], MMP-9 [139, 142, 155], MMP-12 [139]

• Mepolizumab (anti-IL-5 Ab)

• Canakinumab (anti-IL-1β Ab)

(Phase 1 clinical trial)

 Inflammatory bowel disease (IBD)

MMP-1 [127], MMP-3 [127], MMP-7 [127, 136], MMP-9 [104, 127], MMP-10 [127], MMP-12 [127], MMP-13 [136]

• Adalimumab/Infliximab/ Golimumab/Certolizumab pegol (anti-TNF-α Ab)

• Vedolizumab (anti-α4β7 integrin Ab)

• Natalizumab (anti-α4 integrin Ab)

• Ustekinumab (anti-IL-12/23 Ab)

Chronic diseases

 Osteoporosis

MMP-1 [10], MMP-2 [10], MMP-9 [10], MMP-13 [10], MMP-14 [10], Cathepsin K [39]

• Denosumab (anti-RANKL Ab)

• Romosozumab (anti-Sclerostin Ab)

 Alzheimer’s disease (AD)

BACE1 [190]

• Aducanumab (anti-Aβ Ab)

(Phase 3 clinical trial)

  1. MMP matrix metalloprotease, ADAM a disintegrin and metalloproteinase, uPA urokinase plasminogen activator, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, EGFR epidermal growth factor receptor, VEGF-A vascular endothelial growth factor A, VEGFR2 vascular endothelial growth factor receptor 2, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, HER2 human epidermal growth factor receptor 2, TNF-α tumor necrosis factor α, IL interleukin, CD cluster of differentiation, IL-6R IL-6 receptor, RANKL receptor activator of nuclear factor kappa-Β ligand, BACE1 β-site amyloid β precursor protein cleaving enzyme 1, Amyloid β