August 5, 2025
Designing a pro-drug is a well-known drug development strategy for small molecule modalities. A chemical moiety is bound to inactivate the small molecule drug. Once administered to a patient, the chemical moiety is cleaved, and the small molecule drug is activated. This same strategy is now being applied to large molecule modalities, such as antibodies, bispecifics, and fusion proteins.
Large molecule modalities such as antibodies, bispecifics, and fusion proteins have a variable region on the molecule that binds to its target. Drug development strategies are now being created to inactivate the large molecule drug, similar to how a pro-drug works. For example, a peptide is bound to the variable region of a large molecule drug to inactivate it by blocking it from binding to its target. Thus, creating a pro-body. However, for the large molecule drug to be activated, the peptide needs to be cleaved from the variable region, allowing the large molecule drug to bind to its target and assert is therapeutic effect.
Activating the pro-body, or cleaving the peptide from the variable region could be accomplished by a protease. A protease is a protein or enzyme in the body that can cleave or break down proteins. If the bonds between the peptide and the large molecule drug are recognized by a protease, then the peptide can be cleaved from the pro-body, activating the large molecule drug.
Ideally, a pro-body would be designed such that it is not activated until it has reached its therapeutic target. For example, if the target is a cell receptor that is expressed on healthy cells and on tumor cells, ideally, the pro-body would only be activated by proteases in the tumor microenvironment.
The promise of a pro-body drug development strategy is that it may lower on-target adverse effects, thus improving the overall therapeutic effectiveness of the large molecule drug.
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