Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Cysteine cathepsins are crucial proteases implicated in various diseases, including cancer.
• Current systemic inhibition strategies face challenges due to off-target effects and toxicity.
• There is a need for targeted therapeutic approaches to selectively inhibit cathepsins.

Purpose of the Study:

• To develop a novel antibody-based platform for targeted delivery of non-natural peptide inhibitors (NNPIs).
• To create selective inhibitors for cysteine cathepsins with potential therapeutic applications.
• To overcome the limitations of systemic protease inhibition.

Main Methods:

• Functionalization of NNPIs with reactive warheads for covalent inhibition.
• Optimization of NNPIs using deep saturation mutagenesis.
• Conjugation of NNPIs to antibodies for cell-type-specific delivery.
• In vitro and in vivo evaluation of antibody-peptide inhibitor conjugates.

Main Results:

• The developed antibody-peptide inhibitor conjugates demonstrated specific inhibition of cathepsin activity in cancer cells and osteoclasts.
• The conjugates exhibited significant therapeutic efficacy in both in vitro and in vivo models.
• The platform enables rapid design and optimization of selective protease inhibitors.

Conclusions:

• The modular antibody-based platform facilitates targeted drug delivery for inhibiting cysteine cathepsins.
• This approach offers a strategy to mitigate side effects associated with systemic inhibition.
• The platform is generalizable for developing targeted inhibitors for various proteases implicated in cancer and other diseases.