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. 2025 Aug 21;32(8):1042-1057.e6.
doi: 10.1016/j.chembiol.2025.07.007.

Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency

Weiyao Wang  1 , Mehman Bunyatov  1 , Deana Moffat  2 , Natalia Lopez-Barbosa  1 , Matthew P DeLisa  3
Affiliations

Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency

Weiyao Wang et al. Cell Chem Biol. .

Abstract

Monoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for basic research and clinical applications. However, high-quality anti-glycan mAbs with sufficiently high affinity and specificity remain scarce, highlighting the need for strategies that enable optimization of antigen-binding properties. To this end, we engineered the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which possesses only modest affinity. Using a combination of rational design and directed evolution, we isolated several affinity-matured IgG variants with ∼5- to 7-fold stronger affinity for polySia relative to mAb735. The higher affinity IgG variants opsonized polySia-positive cancer cells more avidly and triggered greater antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Collectively, these results demonstrate the effective application of molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition and uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.

Keywords: TACA; affinity maturation; cancer; capsular polysaccharides; directed evolution; glycoprotein; glycosylation; monoclonal antibodies; tumor-associated carbohydrate antigen; yeast surface display.

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Conflict of interest statement

Declaration of interests Competing financial interests. M.P.D. has financial interests in June Bio APS, Gauntlet, Inc. Glycobia, Inc., Resilience, Inc. MacImmune, Inc., UbiquiTx, Inc., and Versatope Therapeutics, Inc. M.P.D.’s interests are reviewed and managed by Cornell University in accordance with their conflict-of-interest policies.

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