Identification of potent biparatopic antibodies targeting FGFR2 fusion–driven cholangiocarcinoma
Saireudee Chaturantabut, Sydney Oliver, Dennie T. Frederick, Jiwan J. Kim, Foxy P. Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J. Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R. Sellers
Saireudee Chaturantabut, Sydney Oliver, Dennie T. Frederick, Jiwan J. Kim, Foxy P. Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J. Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R. Sellers
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Research Article Oncology

Identification of potent biparatopic antibodies targeting FGFR2 fusion–driven cholangiocarcinoma

Abstract

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to suboptimal dosing, relating to drug adverse effects. Here, we develop biparatopic antibodies targeting the FGFR2 extracellular domain (ECD) as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2 fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, we believe that biparatopic antibodies may serve as an innovative treatment option for patients with FGFR2-altered cholangiocarcinoma.

Authors

Saireudee Chaturantabut, Sydney Oliver, Dennie T. Frederick, Jiwan J. Kim, Foxy P. Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J. Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R. Sellers

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Figure 5

Biparatopic antibodies show superior in vivo antitumor activity compared with the parental antibodies.

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Biparatopic antibodies show superior in vivo antitumor activity compared...
(A–D) Tumors of BALB/c scid mice (n = 10 per group) harboring BaF3 cells overexpressing FGFR2-PHGDH (A and B) or ICC13-7 (C and D) subcutaneous xenografts treated with parental and biparatopic antibodies. Results are represented in the waterfall plot illustrating changes in tumor volume at day 25 (A and B) or day 38 (C and D) after initial treatment (A and C) and as geometric mean of tumor volumes ± SEM every 3–4 days from days 0–25 after initial treatment (B and D). Data are mean ± SEM across 10 mice. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Friedman’s ANOVA multiple comparisons. (E) Immunoblot analysis of FGFR2-PHGDH–overexpressing BaF3 cells xenograft tumors harvested 5 hours after the final round of bpAb-B/C, bpAb-B/D, or IgG1 administration at 25 days after initial treatment. (F) Immunoblot analysis of ICC13-7 xenograft tumors collected 5 hours after the final round of antibody administration on day 38 after initial treatment. (G) Representative images of H&E and IHC staining for proliferation marker Ki-67 in ICC13-7 xenograft tumor samples on the final day of treatment. Scale bars, 100 μm. (H) Quantification of the percent of Ki-67–positive nuclei normalized to the total number of nuclei (nuclei counterstain). Data are from 2 biological replicates per treatment group with at least 14 representative images for analysis per group. Data are presented in a superplot where each color represents data points from the same biological sample. Black dots indicate the average values for each biological sample, while black lines represent the overall average for all data points. All data are mean ± SEM. One independent experiment was performed.