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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity
BinQing Wei1, Janet Gunzner-Toste1, Hui Yao2
1Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.
Insights
Novel nonpeptidic linkers enhance antibody-drug conjugates (ADCs) by improving tumor-specific protease cleavage. This discovery offers new opportunities for safer and more selective cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Bioconjugation
Background:
- Antibody-drug conjugates (ADCs) are vital oncology therapeutics, but improving their therapeutic index remains crucial.
- Current peptide-based ADC linkers offer serum stability and cellular payload release but lack protease specificity.
- Tumor-specific protease hydrolysis of ADC linkers could enhance safety margins.
Purpose of the Study:
- To discover and characterize novel, nonpeptidic ADC linkers with improved protease specificity.
- To evaluate the in vivo efficacy and stability of ADCs utilizing these new linkers.
Main Methods:
- Structure-guided design of nonpeptidic linkers.
- Synthesis of cyclobutane-1,1-dicarboxamide-containing linkers.
- In vitro hydrolysis assays using cathepsin B.
- In vivo efficacy and stability studies of ADCs.
Main Results:
- A novel cyclobutane-1,1-dicarboxamide linker demonstrated predominant hydrolysis by cathepsin B.
- The nonpeptidic linker exhibited comparable in vivo efficacy and stability to traditional valine-citrulline dipeptide linkers.
- The valine-citrulline dipeptide linker showed no significant hydrolysis by cathepsin B.
Conclusions:
- Nonpeptidic, peptidomimetic linkers can be designed for selective protease cleavage, specifically by cathepsin B.
- These novel linkers maintain ADC efficacy and stability, offering a promising alternative to peptide-based linkers.
- The findings open new avenues for developing more selective and safer ADCs in cancer therapy.
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