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Rapid Antibody Glycoengineering in Chinese Hamster Ovary Cells
Published on: June 2, 2022
Directed Evolution of Therapeutic Antibodies Targeting Glycosylation in Cancer
Ron Amon1, Ronit Rosenfeld2, Shahar Perlmutter1,3
1Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, The Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
Glycosylation patterns commonly change in cancer, resulting in expression of tumor-associated carbohydrate antigens (TACA). While promising, currently available anti-glycan antibodies are not useful for clinical cancer therapy. Here, we show that potent anti-glycan antibodies can be engineered to acquire cancer therapeutic efficacy. We designed yeast surface display to generate and select for therapeutic antibodies against the TACA SLea (CA19-9) in colon and pancreatic cancers. Elite clones showed increased affinity, better specificity, improved binding of human pancreatic and colon cancer cell lines, and increased complement-dependent therapeutic efficacy. Molecular modeling explained the structural basis for improved antibody functionality at the molecular level. These new tools of directed molecular evolution and selection for effective anti-glycan antibodies, provide insights into the mechanisms of cancer therapy targeting glycosylation, and provide major methodological advances that are likely to open up innovative avenues of research in the field of cancer theranostics.
Insights
Researchers engineered potent anti-glycan antibodies for cancer therapy. These antibodies target tumor-associated carbohydrate antigens (TACA) like SLea, showing improved efficacy against colon and pancreatic cancers.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Aberrant glycosylation is a hallmark of cancer, leading to the expression of tumor-associated carbohydrate antigens (TACA).
- Current anti-glycan antibodies lack the specificity and potency for effective clinical cancer therapy.
- Targeting TACA presents a promising strategy for cancer treatment and diagnostics.
Purpose of the Study:
- To engineer potent therapeutic antibodies against the TACA SLea (CA19-9) for colon and pancreatic cancers.
- To enhance antibody affinity, specificity, and therapeutic efficacy using directed evolution.
- To investigate the structural basis for improved antibody functionality.
Main Methods:
- Yeast surface display was employed for the generation and selection of therapeutic antibodies.
- Directed molecular evolution was used to optimize antibody binding and effector functions.
- Molecular modeling was utilized to elucidate the structural mechanisms underlying antibody improvements.
Main Results:
- Engineered antibodies demonstrated increased affinity and specificity for the TACA SLea.
- Selected antibody clones exhibited enhanced binding to human colon and pancreatic cancer cell lines.
- Improved complement-dependent cytotoxicity was observed, indicating enhanced therapeutic efficacy.
Conclusions:
- Potent anti-glycan antibodies with therapeutic efficacy can be engineered against TACA.
- Directed evolution and selection are powerful tools for developing targeted cancer therapies.
- These advancements offer new avenues for cancer theranostics by targeting glycosylation.
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