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Anti‑HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma.

ABSTRACT: HER3 belongs to the epidermal growth factor receptor (EGFR) family and is known to form an active heterodimer with other three family members EGFR, HER2, and HER4. HER3 is overexpressed in lung, breast, colon, prostate, and gastric cancers. In the present study, we developed and validated an anti‑HER3 monoclonal antibody (mAb), H₃Mab‑17 (IgG_2a, kappa), by immunizing mice with HER3‑overexpressed CHO‑K1 cells (CHO/HER3). H₃Mab‑17 was found to react specifically with endogenous HER3 in colorectal carcinoma cell lines, using flow cytometry. The K_D for H₃Mab‑17 in CHO/HER3 and Caco‑2 (a colon cancer cell line) were determined to be 3.0x10^‑9 M and 1.5x10^‑9 M via flow cytometry, respectively, suggesting high binding affinity of H₃Mab‑17 to HER3. Then, we assessed the H₃Mab‑17 antibody‑dependent cellular cytotoxicity (ADCC) and complement‑dependent cytotoxicity (CDC) against Caco‑2, and evaluated its antitumor capacity in a Caco‑2 xenograft model. In vitro experiments revealed H₃Mab‑17 had strongly induced both ADCC and CDC against Caco‑2 cells. In vivo experiments on Caco‑2 xenografts revealed that H₃Mab‑17 treatment significantly reduced tumor growth compared with the control mouse IgG. These data indicated that H₃Mab‑17 could be a promising treatment option for HER3‑expressing colon cancers.

SUBMITTER: Asano T

PROVIDER: S-EPMC8261196 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CD44 is widely expressed on the surface of most tissues and all hematopoietic cells, and regulates many genes associated with cell adhesion, migration, proliferation, differentiation, and survival. CD44 has also been studied as a therapeutic target in several cancers. Previously, an anti‑CD44 monoclonal antibody (mAb), C44Mab‑5 (IgG1, kappa) was established by immunizing mice with CD44‑overexpressing Chinese hamster ovary (CHO)-K1 cells. C44Mab‑5 recognized all CD44 isoforms, and showed high sensitivity for flow cytometry and immunohistochemical analysis in oral cancers. However, as the IgG1 subclass of C44Mab‑5 lacks antibody‑dependent cellular cytotoxicity (ADCC) and complement‑dependent cytotoxicity (CDC), the antitumor activity of C44Mab‑5 could not be determined. In the present study, we converted the mouse IgG1 subclass antibody C44Mab‑5 into an IgG2a subclass antibody, 5‑mG2a, and further produced a defucosylated version, 5‑mG2a‑f, using FUT8‑deficient ExpiCHO‑S (BINDS‑09) cells. Defucosylation of 5‑mG2a‑f was confirmed using fucose‑binding lectins, such as AAL and PhoSL. The dissociation constants (KD) for 5‑mG2a‑f against SAS and HSC‑2 oral cancer cells were determined through flow cytometry to be 2.8x10‑10 M and 2.6x10‑9 M, respectively, indicating that 5‑mG2a‑f possesses extremely high binding affinity. Furthermore, immunohistochemical staining using 5‑mG2a‑f specifically stained the membranes of oral cancer cells. In vitro analysis demonstrated that 5‑mG2a‑f showed moderate ADCC and CDC activities against SAS and HSC‑2 oral cancer cells. In vivo analysis revealed that 5‑mG2a‑f significantly reduced tumor development in SAS and HSC‑2 xenografts in comparison to control mouse IgG, even after injection seven days post‑tumor inoculation. Collectively, these results suggest that treatment with 5‑mG2a‑f may represent a useful therapy for patients with CD44‑expressing oral cancers.

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Anti‑HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma.

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