Antibodies targeting sialyl Lewis A mediate tumor clearance through distinct effector pathways
Polina Weitzenfeld, … , Stylianos Bournazos, Jeffrey V. Ravetch
Polina Weitzenfeld, … , Stylianos Bournazos, Jeffrey V. Ravetch
Published August 19, 2019
Citation Information: J Clin Invest. 2019;129(9):3952-3962. https://doi.org/10.1172/JCI128437.
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Research Article Immunology

Antibodies targeting sialyl Lewis A mediate tumor clearance through distinct effector pathways

Abstract

Sialyl Lewis A (sLeA, also known as CA19-9), a tetrasaccharide selectively and highly expressed on advanced adenocarcinomas including colon, stomach, and pancreatic cancers, has long been considered as an attractive target for active and passive vaccination. While progress in antibodies targeting tumor-associated protein antigens resulted in an impressive array of therapeutics for cancer treatment, similar progress in exploiting tumor-associated carbohydrate antigens, such as sLeA, has been hampered by the lack of a detailed understanding of the singular characteristics of these antigens. We have addressed this issue by analyzing antibodies derived from patients immunized with an sLeA/KLH vaccine. These antibodies were engineered to mediate tumor clearance in vivo in preclinical models through Fc-FcγR interactions. However, in contrast to protein antigens in which hFcγRIIIA engagement was both necessary and sufficient to mediate tumor clearance in both preclinical and clinical settings, a similar selective dependence was not seen for anti-sLeA antibodies. Thus, re-engineering the Fc portion of sLeA-targeting antibodies to broadly enhance their affinity for activating FcγRs led to an enhanced therapeutic effect. These findings will facilitate the development of more efficient anticancer therapies and further advance this promising class of therapeutic antibodies into clinical use.

Authors

Polina Weitzenfeld, Stylianos Bournazos, Jeffrey V. Ravetch

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Figure 2

sLeA-targeting Abs protect mice from sLeA+ tumor challenge.

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sLeA-targeting Abs protect mice from sLeA+ tumor challenge. (A) Anti-sLe...
(A) Anti-sLeA Abs inhibit lung colonization of sLeA+ B16 cells. WT C57BL/6 mice were inoculated i.v. with 5 × 105 B16 or B16-FUT3 tumor cells. One hundred micrograms of anti-sLeA Abs (5B1-mIgG2a or 7E3-mIgG2a) or isotype-matched control Abs was administered i.p. on days 1, 4, 7, and 11. Fourteen days after inoculation, mice were euthanized, lungs were excised and fixed, and metastatic foci were counted. The panel summarizes data pooled from n = 3 experiments, and shows representative images of 3 excised lungs from mice inoculated with B16-FUT3 cells. n > 20 for all groups, except 7E3-mIgG2a (n = 6–8/group). **P < 0.01, ****P < 0.0001 (1-way ANOVA with Bonferroni’s post hoc test). The box extends from the 25th to 75th percentile, the line within the box represents the median value, and the whiskers correspond to the 5th to 95th percentile. (B) Anti-sLeA Abs rescue mice inoculated with sLeA+ EL4 cells. WT C57BL/6 mice were inoculated i.v. with 5 × 105 EL4 or EL4-FUT3 tumor cells. One hundred micrograms of anti-sLeA Abs (B1: 5B1-mIgG2a; B2: 7E3-mIgG2a) or isotype-matched control Abs was administered i.p. on days 1, 4, 7, and 11. Survival was assessed daily. For 5B1, data were pooled from n = 2 experiments, n > 20/group. For 7E3, n = 10–20/group. ****P < 0.0001 (log-rank test). NS, not significant.