From: Ab locks for improving the selectivity and safety of antibody drugs
Ab lock (MW) | Masking theory | Example Ab (Refs) | Schematic |
---|---|---|---|
Spatial hindrance-based Ab lock | |||
Autologous hinge domain (3.5 kDa) | Human IgG1 hinge forms disulfide bond for sterically interfering with the antigen binding ability of Ab drugs | • Infliximab (anti-TNF-α mAb) [100] | |
Coiled-coil (CC) domain (5 ~ 9.2 kDa) | Covalent and non-covalent CC domains and helix-turn-helix domains derived from de novo designs or native human proteins (e.g. c-Fos and c-Jun) can form a robust secondary structure and sterically block the CDRs of Ab drugs from binding antigen | • anti-CD19 Ab (clone hBU12) [176] | |
• Rituximab (anti-CD20 mAb) [176] | |||
• Trastuzumab (anti-HER2 mAb) [176] | |||
• h15H3 (anti-αVβ6 mAb) [176] | |||
• 145-2C11 (anti-mouse CD3 mAb) [176] | |||
Non-Ab protein fragment (40 kDa) | Latency-associated peptide (LAP) derived from transforming growth factor-β (TGF-β) sterically interferes the antigen binding ability of Ab drugs | • Cetuximab (anti-EGFR Ab) [27] | |
• Infliximab [27] | |||
Ab fragment (26 kDa) | The outer disulfide-stabilized variable fragment (dsFv) or whole Ab, which against specific antigen, can shield the inner antigen binding domain of another Ab drug | • anti-c-Met dsFv [108] | |
• Infliximab • Adalimumab (anti-TNF-α mAb) [124] | |||
• anti-CTLA-4 Ab (clone 24H2) [125] | |||
Affinity peptide-based Ab lock | |||
Affinity peptide (2.8 ~ 5 kDa) | Binding peptide from bacterial peptide display library that could specifically occupy the antigen-binding site of Ab drug | • Cetuximab [35] | |
• anti-VCAM-1 Ab [43] | |||
• Panitumumab (anti-EGFR mAb) [193] | |||
• anti-HIV p17 Ab [70] | |||
Mutated antigen (23.3 kDa) | Point mutated soluble EGFR domain III (sEGFRdIII) can be bound by anti-EGFR Ab, thereby masking its antigen binding ability in the condition without protease presentation | • Cetuximab [36] • Matuzumab (anti-EGFR mAb) [36] |