Development of masked therapeutic antibodies to limit off-target effects
In one embodiment, a masked monoclonal antibody (mAb) is provided, the mAb, encoded by a nucleic acid sequence or an amino acid sequence molecule comprising a signal sequence, a masking epitope sequence, a linker sequence that is cleavable by a protease specific to a target tissue; and an antibody or a functional fragment thereof. In another embodiment, a masked monoclonal antibody (mAb) is provided, which includes a therapeutic mAb and a mask, the mask comprising protein A and protein L attached by a protease cleavable linker.
1. A mask molecule comprising domain IV of a HER2 receptor which binds to trastuzumab monoclonal antibody (mAb) or an antigen-binding fragment thereof and an Fc portion of an IgG1 molecule connected by a linker comprising VPLSLYS (SEQ ID NO: 3) that is cleavable by a matrix metalloproteinase-9 (MMP-9) protease specific to a target tissue.
2. The masked molecule of claim 1 , wherein the linker is SEQ ID NO:7.
3. The masked molecule of claim 1 , wherein the linker is SEQ ID NO:4.
4. The mask molecule of claim 1 further binds to trastuzumab mAb or the antigen-binding fragment thereof to form a masked trastuzumab or antigen-binding fragment thereof.