Journal
THERANOSTICS
Volume 11, Issue 18, Pages 9107-9117Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.62444
Keywords
Antibody-drug conjugates; Bispecific antibodies; Proximity-Induced Chemistry; Site-specific conjugation; Antibody Conjugation
Categories
Funding
- National Key R&D Program of China [2019YFA0904200, 2019YFA0906100]
- National Natural Science Foundation of China [81872783]
- Guangdong Natural Science Foundation [2018A030313916]
- Shenzhen Science and Technology Innovation Program [JCYJ201805 04165501371, JCYJ20170818090043031]
- Cancer Prevention Research Institute of Texas [CPRIT RR170014]
- Robert A. Welch Foundation [C-1970]
- Genentech, Inc
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The pClick technology offers a simple and efficient method to prepare homogeneous antibody conjugates from native antibodies without the need for additional engineering or treatments. The resulting conjugates exhibit excellent antitumor activity and cytotoxic effects, providing a convenient strategy for developing novel antibody conjugates.
Rationale: Therapeutic antibody conjugates allow for the specific delivery of cytotoxic agents or immune cells to tumors, thus enhancing the antitumor activity of these agents and minimizing adverse systemic effects. Most current antibody conjugates are prepared by nonspecific modification of antibody cysteine or lysine residues, inevitably resulting in the generation of heterogeneous conjugates with limited therapeutic efficacies. Traditional strategies to prepare homogeneous antibody conjugates require antibody engineering or chemical/enzymatic treatments, processes that often affect antibody folding and stability, as well as yield and cost. Developing a simple and cost-effective way to precisely couple functional payloads to native antibodies is of great importance. Methods: We describe a simple proximity-induced antibody conjugation method (pClick) that enables the synthesis of homogeneous antibody conjugates from native antibodies without requiring additional antibody engineering or post-synthesis treatments. A proximity-activated crosslinker is introduced into a chemically synthesized affinity peptide modified with a bioorthogonal handle. Upon binding to a specific antibody site, the affinity peptide covalently attaches to the antibody via spontaneous crosslinking, yielding an antibody molecule ready for bioorthogonal conjugation with payloads. Results: We have prepared well-defined antibody-drug conjugates and bispecific small molecule-antibody conjugates using pClick technology. The resulting conjugates exhibit excellent in vitro cytotoxic activity against cancer cells and, in the case of bispecific conjugates, superb antitumor activity in mouse xenograft models. Conclusions: Our pClick technology enables efficient, simple, and site-specific conjugation of various moieties to the existing native antibodies. This technology does not require antibody engineering or additional UV/chemical/enzymatic treatments, therefore providing a general, convenient strategy for developing novel antibody conjugates.
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